Pediatricians' preferences for infant meningococcal vaccination.

BACKGROUND: Meningococcal disease is rare but can cause death or disabilities. Although the Advisory Committee on Immunization Practices has recommended meningococcal vaccination for at-risk children aged 9 through 23 months, it has not endorsed universal vaccination. Health insurance payments for the vaccination of children who are not at risk are likely to be limited. Use of infant meningococcal vaccines by these families will thus depend on the preferences of physicians who might recommend vaccination to parents, as well as parents' preferences. OBJECTIVE: To quantify pediatricians' preferences for specific features of hypothetical infant meningococcal vaccines. METHODS: A sample of pediatricians (n = 216) completed a Web-enabled, discrete choice experiment survey in which respondents chose between pairs of hypothetical vaccines in a series of trade-off questions. The questions described vaccines with six attributes. A random-parameters logit regression model was used to estimate the relative importance weights physicians place on vaccine features. These weights were used to calculate the predicted probability that a physician chooses hypothetical vaccines with given characteristics. RESULTS: Pediatricians' choices indicated that increases in vaccine effectiveness were among the most important factors in their vaccine recommendations, followed by increases in the number of injections. The age at which protection begins and the number of additional office visits were less important. Whether a booster was required after 5 years was the least important factor in vaccine recommendations. The results suggest that virtually all (99.9%) physicians in the sample would recommend a vaccine even with the least-preferred features rather than no infant meningococcal vaccine. CONCLUSIONS: Physicians' responses indicate a strong preference for infant meningococcal vaccination.

Evaluation of serogroup C and ACWY meningococcal vaccine programs: projected impact on disease burden according to a stochastic two-strain dynamic model.

OBJECTIVE: Advisory committees in Canada and the United States have updated recommendations for quadrivalent meningococcal conjugate vaccines against serogroups A, C, W135, and Y. Our objective was to evaluate optimally effective meningococcal vaccination policies using a stochastic dynamic model. Canada was used as an example. METHODS: Our stochastic dynamic model of Neisseria meningitidis (Nm) transmission in an age-structured population assumed partial cross-immunity among two aggregated serogroup categories: 'AWY' containing A, W135, and Y; and 'Other' containing B, C, and ungroupable types. We compared the impact of monovalent C versus quadrivalent ACWY vaccination on Nm carriage and invasive meningococcal disease (IMD). Our model was parameterized with Canadian epidemiological and demographic data and employed probabilistic sensitivity analysis. RESULTS: Routine infant immunization at 12 months and boosting at 15 years with a quadrivalent vaccine is projected to have the largest impact on total IMD incidence: a 74% reduction over 40 years. Routine infant immunization with a monovalent vaccine at 12 months only has much less impact and also generates strain replacement appearing after approximately ten years of continuous use. CONCLUSIONS: Immunizing infants at 12 months and boosting adolescents at 15 years with an ACWY vaccine is predicted to be most effective at reducing IMD incidence.

The burden and impact of severe and long-term sequelae of meningococcal disease.

This review describes current knowledge on the severity and long-term sequelae of meningococcal disease (MD) specifically. The literature databases Medline and Embase were used by combining search terms for MD and Neisseria meningitidis with terms for severity, mortality and sequelae. Case fatality for sufferers of MD remains high, typically 5-10%, despite the best medical care. Long-term sequelae in survivors may include physical, neurological, cognitive, behavioral and psychological consequences, such as hearing loss, amputations, skin scarring and neurodevelopmental deficits. A significantly lower quality of life is seen in survivors of MD compared with unaffected controls, with detrimental effects of childhood MD continuing into adulthood. MD carries a substantial risk of long-term sequelae and mortality. This should be recognized by physicians treating patients with this disease and lends support for the implementation of preventative measures such as vaccination.

The cost and public health burden of invasive meningococcal disease outbreaks: a systematic review.

BACKGROUND: Invasive meningococcal disease (IMD) is a serious disease with a rapid onset, high mortality rate, and risk of long-term complications. Numerous reports in the literature conclude that IMD outbreaks are associated with substantial costs to society and significant burden on communities due to the cost associated with the prevention of secondary cases. OBJECTIVE: To systematically review the literature on the costs and public health burden associated with IMD outbreaks. METHODS: Studies were primarily identified through searching MEDLINE and EMBASE. Reports were included if they provided cost data related to the containment of an IMD outbreak after 1990 and were written in English, French, or Spanish. Costs were converted to 2010 United States dollars. Outbreaks were categorized by low-income countries (LIC) and high-income countries (HIC) based on gross domestic product per capita. Outbreak containment strategies were classified as small (e.g., targeting members of the school/institution where the outbreak occurred) or large (e.g., targeting everyone in the community). RESULTS: Sixteen articles reporting data on 93 IMD outbreaks fulfilled the eligibility criteria and were included. The majority of outbreaks occurred in HIC. Five studies reported the use of small containment strategies including targeted vaccination and chemoprophylaxis, all occurring in HIC. The average cost per small containment strategy was $299,641 and the average cost per IMD case was $41,857. Eight studies reported large containment strategies involving widespread vaccination targeting a specific age group or community. For HIC, the average cost per large containment strategy was $579,851 and the average cost per IMD case was $55,755. In LIC, the average cost per large containment strategy was $3,407,590 and the average cost per IMD case was $2,222. CONCLUSION: IMD outbreaks were associated with substantial costs. We found that although there were numerous reports on IMD outbreaks, data on containment costs were very limited. More research in this area is warranted.

Modeling the impact of the difference in cross-protection data between a human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and a human papillomavirus (HPV)-6/11/16/18 vaccine in Canada.

BACKGROUND: In Canada, two vaccines that have demonstrated high efficacy against infection with human papillomavirus (HPV) types -16 and -18 are available. The HPV-6/11/16/18 vaccine provides protection against genital warts (GW) while the HPV-16/18 vaccine may provide better protection against other oncogenic HPV types. In this analysis, the estimated clinical and economic benefit of each of these vaccines was compared in the Canadian setting. METHODS: A Markov model of the natural history of HPV infection among women, cervical cancer (CC) and GW was used to estimate the impact of vaccinating a cohort of 100,000 12-year-old females on lifetime outcomes and healthcare system costs (no indirect benefit in males included). A budget impact model was used to estimate the impact of each vaccine by province. RESULTS: In the base case, vaccination with the HPV-16/18 vaccine was predicted to prevent 48 additional CC cases, and 16 additional CC deaths, while vaccination with the HPV-6/11/16/18 vaccine was predicted to prevent 6,933 additional GW cases. Vaccination with the HPV-16/18 vaccine was estimated to save 1 additional discounted quality adjusted life year (QALY) at an overall lower lifetime cost to the healthcare system compared to the HPV-6/11/16/18 vaccine (assuming vaccine price parity). In sensitivity analyses, the HPV-6/11/16/18 vaccine was associated with greater QALYs saved when the cross-protection efficacy of the HPV-16/18 vaccine was reduced, or the burden of GW due to HPV-6/11 was increased. In most scenarios with price parity, the lifetime healthcare cost of the strategy with the HPV-16/18 vaccine was predicted to be lower than the HPV-6/11/16/18 vaccine. In the probabilistic sensitivity analyses, the HPV-16/18 vaccine provided more QALY benefit than the HPV-6/11/16/18 vaccine in 49.2% of scenarios, with lower relative lifetime costs in 83.5% of scenarios. CONCLUSIONS: Overall, the predicted lifetime healthcare costs and QALYs saved by implementing each of the vaccines are similar. Vaccination with the HPV-16/18 vaccine is expected to be associated with reduced CC disease morbidity and mortality compared to vaccination with the HPV-6/11/16/18 vaccine. Differences in these outcomes depend on the extent of cervical disease prevented by cross-protection and the burden of GW caused by HPV-6/11.

Use of a catalytic model to estimate hepatitis A incidence in a low-endemicity country: implications for modeling immunization policies.

BACKGROUND: Evaluating the cost-effectiveness of vaccine programs with dynamic modeling requires accurate estimates of incidence over time. Because infectious diseases are often underreported, supplementary data and statistical analyses are required to estimate true incidence. This study estimates the true incidence of hepatitis A virus (HAV) infection in Canada using a catalytic model. METHODS: A catalytic model was used to reconcile HAV seroprevalence data with the corresponding true cumulative risk of infection estimated from incidence data. RESULTS: The average annual reported incidence was 6.2 cases per 100,000 from 1980 to 1989 and 7.7/100,000 from 1990 to 1999, indicating that Canada is a low-incidence country. The seroprevalence in Canadian-born individuals (n = 7 studies) was approximately 1%-8% in ages <20, 1%-11% in ages 20-29, 7%-29% in ages 30-39, and higher in older age groups. Between 1980 and 1995, the catalytic model estimated an average annual incidence of 60/100,000 (95% confidence interval, 33-524); approximately 7.73 (4.21-67.33) times the average annual reported incidence of 7.78/100,000. For a typical birth cohort of 403 434 Canadians born in 1990, the model predicted 32 750 HAV cases by age 39, with a corresponding seroprevalence of approximately 8.12% by the year 2029. IMPLICATIONS: Reliable estimates of true incidence of infectious disease are required for cost-effectiveness analysis of infectious disease programs. Catalytic models enable the synthesis of dispersed data, quantification of data limitations, and reconciliation of these limitations to estimate true incidence for economic evaluations.

Time for change? An economic evaluation of integrated cervical screening and HPV immunization programs in Canada.

Many jurisdictions have implemented universal human papillomavirus (HPV) immunization programs in preadolescent females. However, the cost-effectiveness of modified cervical screening guidelines and/or catch-up immunization in older females in Canada has not been evaluated. We conducted a cost-utility analysis of screening and immunization with the bivalent vaccine for the Canadian setting from the Ministry of Health perspective. We used a dynamic model to capture herd immunity and included cross-protection against strains not included in the vaccine. We found that adding catch-up immunization to the current program would be cost-effective, and that combining catch-up immunization with delaying the age at which screening is first initiated could result in cost savings and net health gains.

Canadian oncogenic human papillomavirus cervical infection prevalence: systematic review and meta-analysis.

BACKGROUND: Oncogenic human papillomavirus (HPV) infection prevalence is required to determine optimal vaccination strategies. We systematically reviewed the prevalence of oncogenic cervical HPV infection among Canadian females prior to immunization. METHODS: We included studies reporting DNA-confirmed oncogenic HPV prevalence estimates among Canadian females identified through searching electronic databases (e.g., MEDLINE) and public health websites. Two independent reviewers screened literature results, abstracted data and appraised study quality. Prevalence estimates were meta-analyzed among routine screening populations, HPV-positive, and by cytology/histology results. RESULTS: Thirty studies plus 21 companion reports were included after screening 837 citations and 120 full-text articles. Many of the studies did not address non-response bias (74%) or use a representative sampling strategy (53%). Age-specific prevalence was highest among females aged < 20 years and slowly declined with increasing age. Across all populations, the highest prevalence estimates from the meta-analyses were observed for HPV types 16 (routine screening populations, 8 studies: 8.6% [95% confidence interval 6.5-10.7%]; HPV-infected, 9 studies: 43.5% [28.7-58.2%]; confirmed cervical cancer, 3 studies: 48.8% [34.0-63.6%]) and 18 (routine screening populations, 8 studies: 3.3% [1.5-5.1%]; HPV-infected, 9 studies: 13.6% [6.1-21.1%], confirmed cervical cancer, 4 studies: 17.1% [6.4-27.9%]. CONCLUSION: Our results support vaccinating females < 20 years of age, along with targeted vaccination of some groups (e.g., under-screened populations). The highest prevalence occurred among HPV types 16 and 18, contributing a combined cervical cancer prevalence of 65.9%. Further cancer protection is expected from cross-protection of non-vaccine HPV types. Poor study quality and heterogeneity suggests that high-quality studies are needed.

A cost-utility analysis of cervical cancer vaccination in preadolescent Canadian females.

BACKGROUND: Despite the fact that approximately 70% of Canadian women undergo cervical cancer screening at least once every 3 years, approximately 1,300 women were diagnosed with cervical cancer and approximately 380 died from it in 2008. This study estimates the effectiveness and cost-effectiveness of vaccinating 12-year old Canadian females with an AS04-adjuvanted cervical cancer vaccine. The indirect effect of vaccination, via herd immunity, is also estimated. METHODS: A 12-health-state 1-year-cycle Markov model was developed to estimate lifetime HPV related events for a cohort of 12-year old females. Annual transition probabilities between health-states were derived from published literature and Canadian population statistics. The model was calibrated using Canadian cancer statistics. From a healthcare perspective, the cost-effectiveness of introducing a vaccine with efficacy against HPV-16/18 and evidence of cross-protection against other oncogenic HPV types was evaluated in a population undergoing current screening practices. The base-case analysis included 70% screening coverage, 75% vaccination coverage, $135/dose for vaccine, and 3% discount rate on future costs and health effects. Conservative herd immunity effects were taken into account by estimated HPV incidence using a mathematical model parameterized by reported age-stratified sexual mixing data. Sensitivity analyses were performed to address parameter uncertainties. RESULTS: Vaccinating 12-year old females (n = 100,000) was estimated to prevent between 390-633 undiscounted cervical cancer cases (reduction of 47%-77%) and 168-275 undiscounted deaths (48%-78%) over their lifetime, depending on whether or not herd immunity and cross-protection against other oncogenic HPV types were included. Vaccination was estimated to cost $18,672-$31,687 per QALY-gained, the lower range representing inclusion of cross-protective efficacy and herd immunity. The cost per QALY-gained was most sensitive to duration of vaccine protection, discount rate, and the correlation between probability of screening and probability of vaccination. CONCLUSION: In the context of current screening patterns, vaccination of 12-year old Canadian females with an ASO4-ajuvanted cervical cancer vaccine is estimated to significantly reduce cervical cancer and mortality, and is a cost-effective option. However, the economic attractiveness of vaccination is impacted by the vaccine's duration of protection and the discount rate used in the analysis.

Incorporating herd immunity effects into cohort models of vaccine cost-effectiveness.

BACKGROUND: Cohort models are often used in cost-effectiveness analysis (CEA) of vaccination. However, because they cannot capture herd immunity effects, cohort models underestimate the reduction in incidence caused by vaccination. Dynamic models capture herd immunity effects but are often not adopted in vaccine CEA. OBJECTIVE: The objective was to develop a pseudo-dynamic approximation that can be incorporated into an existing cohort model to capture herd immunity effects. METHODS: The authors approximated changing force of infection due to universal vaccination for a pediatric infectious disease. The projected lifetime cases in a cohort were compared under 1) a cohort model, 2) a cohort model with pseudo-dynamic approximation, and 3) an age-structured susceptible-exposed-infectious-recovered compartmental (dynamic) model. The authors extended the methodology to sexually transmitted infections. RESULTS: For average to high values of vaccine coverage (P > 60%) and small to average values of the basic reproduction number (R(0) < 10), which describes school-based vaccination programs for many common infections, the pseudo-dynamic approximation significantly improved projected lifetime cases and was close to projections of the full dynamic model. For large values of R(0) (R(0) > 15), projected lifetime cases were similar under the dynamic model and the cohort model, both with and without pseudo-dynamic approximation. The approximation captures changes in the mean age at infection in the 1st vaccinated cohort. CONCLUSIONS: This methodology allows for preliminary assessment of herd immunity effects on CEA of universal vaccination for pediatric infectious diseases. The method requires simple adjustments to an existing cohort model and less data than a full dynamic model.

Comparison of detailed and succinct cohort modelling approaches in a multi-regional evaluation of cervical cancer vaccination.

Mathematical models have been used extensively in the evaluation of chronic diseases and in exploring the health economics of vaccination. In this study, we examine the value of having two different cohort models based on similar assumptions, one comprehensive and one simplified, which can be used to evaluate the impact of cervical cancer vaccination. To compare models, we ran cost-effectiveness analyses in four geographical regions (Italy, the UK, Taiwan and Canada). We show that the models produce comparable results and therefore can be used independently. However, as they require different complexities of data inputs, they are more suited to different circumstances depending on the level of data inputs available or the complexity of the research question asked.

Luteal phase administration of paroxetine for the treatment of premenstrual dysphoric disorder: a randomized, double-blind, placebo-controlled trial in Canadian women.

OBJECTIVE: To evaluate the efficacy and safety of intermittent, luteal phase-only administration of paroxetine (10 mg and 20 mg) in the treatment of premenstrual dysphoric disorder (PMDD). METHOD: In this multicenter trial, female outpatients (aged 18-45 years) from 4 Canadian health centers meeting DSM-IV criteria for PMDD were asked to perform daily ratings of their premenstrual symptoms for 2 consecutive menstrual cycles. Those displaying the symptoms of irritability and/or depressed mood in the luteal phases but not in the follicular phases of their menstrual cycles were randomly assigned to intermittent, luteal phase-only treatment with paroxetine 10 mg or 20 mg or placebo for 4 additional cycles. The primary efficacy endpoint was the percent change from baseline at study endpoint on the visual analog scale irritability score. Treatment differences were tested using analysis of covariance ad hoc. Estimated treatment mean differences and their associated 95% confidence intervals were also calculated. Data were collected from May 1999 to November 2002. RESULTS: Ninety-nine patients were included in the intention-to-treat population. When compared with placebo, patients treated with paroxetine 20 mg attained a significant reduction in irritability (difference in median percent change: -23.9, 95% CI = -51.3 to -6.2, p = .014; difference in mean absolute change: -18.6, 95% CI = -32.5 to -4.6, p = .007). A statistically significant difference was not observed when the patients treated with the lower dose of paroxetine (10 mg) were compared with placebo. Treatment was well tolerated with no unexpected side effects. CONCLUSIONS: Intermittent administration of paroxetine 20 mg significantly reduced irritability symptoms in patients with PMDD. These results are consistent with previous studies suggesting that PMDD may be treated effectively by luteal phase-only administration of a selective serotonin reuptake inhibitor. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00620581.

Cost-effectiveness analyses of hepatitis A vaccine: a systematic review to explore the effect of methodological quality on the economic attractiveness of vaccination strategies.

Hepatitis A vaccines have been available for more than a decade. Because the burden of hepatitis A virus has fallen in developed countries, the appropriate role of vaccination programmes, especially universal vaccination strategies, remains unclear. Cost-effectiveness analysis is a useful method of relating the costs of vaccination to its benefits, and may inform policy. This article systematically reviews the evidence on the cost effectiveness of hepatitis A vaccination in varying populations, and explores the effects of methodological quality and key modelling issues on the cost-effectiveness ratios.Cost-effectiveness/cost-utility studies of hepatitis A vaccine were identified via a series of literature searches (MEDLINE, EMBASE, HSTAR and SSCI). Citations and full-text articles were reviewed independently by two reviewers. Reference searching, author searches and expert consultation ensured literature saturation. Incremental cost-effectiveness ratios (ICERs) were abstracted for base-case analyses, converted to $US, year 2005 values, and categorised to reflect various levels of cost effectiveness. Quality of reporting, methodological issues and key modelling issues were assessed using frameworks published in the literature.Thirty-one cost-effectiveness studies (including 12 cost-utility analyses) were included from full-text article review (n = 58) and citation screening (n = 570). These studies evaluated universal mass vaccination (n = 14), targeted vaccination (n = 17) and vaccination of susceptibles (i.e. individuals initially screened for antibody and, if susceptible, vaccinated) [n = 13]. For universal vaccination, 50% of the ICERs were <$US20 000 per QALY or life-year gained. Analyses evaluating vaccination in children, particularly in high incidence areas, produced the most attractive ICERs. For targeted vaccination, cost effectiveness was highly dependent on the risk of infection.Incidence, vaccine cost and discount rate were the most influential parameters in sensitivity analyses. Overall, analyses that evaluated the combined hepatitis A/hepatitis B vaccine, adjusted incidence for under-reporting, included societal costs and that came from studies of higher methodological quality tended to have more attractive cost-effectiveness ratios. Methodological quality varied across studies. Major methodological flaws included inappropriate model type, comparator, incidence estimate and inclusion/exclusion of costs.

A review of interventions triggered by hepatitis A infected food-handlers in Canada.

BACKGROUND: In countries with low hepatitis A (HA) endemicity, infected food handlers are the source of most reported foodborne outbreaks. In Canada, accessible data repositories of infected food handler incidents are not available. We undertook a systematic review of such incidents to evaluate the extent of viral transmission through food contamination and the scope of post-exposure prophylaxis (PEP) interventions. METHODS: A systematic search of MEDLINE and EMBASE was conducted to identify published reports of incidents in Canada. An expanded search of a news repository (i.e., transcripts from newspapers and newscasts) was also conducted to identify the location and timing of an incident, which was used to retrieve the related report by contacting local public health departments. Data pertaining to case identification, public health risk, PEP interventions, and associated costs was independently abstracted by two reviewers and summarized according to incidents with and without large PEP interventions. RESULTS: A total of 16 incidents were identified from 1998-2004. There were approximately 3 incidents requiring public notification per year. Only 12.5% of incidents were described in published reports, indicating that published data significantly underestimated the number of incidents and PEP interventions. Data pertaining to the remaining incidents was unpublished, sparse and highly dispersed at the local public health level. Six of the 16 incidents required large PEP interventions to immunize on average 5000 potentially exposed individuals. Secondary transmission was low. Characteristics of incidents requiring large PEP interventions included potentially infectious food handlers working with uncooked food for a prolonged duration in high-volume grocery stores in high-density urban areas. CONCLUSION: Infected food handlers with hepatitis A virus (HAV) requiring public notification are not infrequent in Canada. Published data severely underestimated the burden of PEP intervention. Better and consistent reporting at the local and national level as well as a national data repository should be considered for the management of future incidents.