A nationwide survey of past hepatitis A infections among Canadian adults.

BACKGROUND: Hepatitis A virus (HAV) infection rates in Canada are low and declining. A nationwide pediatric serosurvey in 2003 confirmed that HAV infection is uncommon in children. Additional seroepidemiological data for adults would help to guide domestic use of HAV vaccines. METHODS: A country-wide survey of HAV antibody positivity and selected risk factors was conducted among 18-69 year olds identified by random digit dialing, in samples proportional to regional populations. Volunteers were sent study materials and returned oral fluid and completed questionnaires by mail. An ultra-sensitive assay was used to detect HAV antibody in oral fluid. Multiple logistic regression was used for risk factor assessment. RESULTS: Of 2104 potential study participants, 1552 (74%) returned an adequate oral fluid specimen and questionnaire. Anti-HAV was detected in 509 individuals (33%) and was associated with birth in HAV endemic areas, self-reported hepatitis A vaccination, prior travel to endemic areas, and increasing age. Only 15% reported having been vaccinated. Among Canadian-born, non-vaccinated participants anti-HAV was present in 20%, ranging regionally from 14% to 30%. Age-specific positivity rates in this subset were: 18-29 years 2.6%; 30-39 years 6.1%; 40-49 years 11.4%; 50-59 years 26.4% and 60-69 years 45.9%. Travel to HAV-endemic countries was reported by 55% of participants but only 24% of travelers had been vaccinated. CONCLUSIONS: Past HAV infection rates among Canadian-born, non-vaccinated individuals are low in young adults and increase by two-fold per age decade. Travel to endemic areas is a significant risk factor, amenable to prevention by greater use of HAV vaccine.

Antibody and immune memory persistence after vaccination of preadolescents with low doses of recombinant hepatitis B vaccine.

Little is known about the impact of low-dose hepatitis B vaccine on the persistence of anti-HBs and immune memory in school-age children. Recombivax-HB 2.5 µg (RB) has been widely used in school-age children. RB induces high seroprotectionrates, but relatively low anti-HBs titers. The main objectives of this phase of the study were to assess anti-HBs persistence and the presence of immune memory 10 years post-vaccination of 8-10 year-old children with 3 doses of RB and the persistence of anti-HBs post-booster dose administration 5 (Group A; n=250) or 10 years (Group B; n=263) post-vaccination. No significant difference was observed between GMTs and the proportion of subjects with anti-HBs titers ≥ 10 mIU/mL 5 or 10 years post-vaccination. In both groups, a 56-fold decrease of anti-HBs GMTs was observed. One month post-booster, all but two subjects in Group A had an anti-HBs titer ≥ 10 mIU/mL. A 4.9- and 11.4-fold decrease in anti-HBs GMTs were observed during the first year post-booster in Group A and B, respectively. One year post-booster, the two groups were equivalent: ≥ 98.8% of subjects had an anti-HBs ≥ 10 mIU/mL. In group A, five years post-booster, 96.8% had a titer ≥ 10 mIU/mL; the GMT was 17-fold higher than the GMT 5 years post-vaccination (p<0.0001). In both groups, there was a strong positive correlation (p<0.0001) between anti-HBs titers observed post-primary vaccination and at following study time points (r=0.70-0.90). Three doses of RB administered at the age of 8-10 years induce a 10 years long-lasting immunity in virtually all vaccinees. The booster does not appear necessary on a 10 years perspective.

Antibody kinetics among 8-10 years old respondents to hepatitis B vaccination in a low endemic country and the effect of a booster dose given 5 or 10 years later.

Few data are available concerning the persistence of anti-HBs and the effect of booster doses given several years post-vaccination against hepatitis B during preadolescence. The objective of this open-labelled clinical trial was to evaluate the persistence of antibodies after vaccination with three paediatric doses of Engerix-B at the age of 8-10 years and the effect of a booster dose given 5 (Group Y5) or 10 (Group Y10) years later. Anti-HBs were measured before and one month post-primary vaccination, then 5 and 10 years later, before the booster dose, as well as one month and 1 year post-booster. The anamnestic response was defined as a >or=fourfold increase of anti-HBs post-booster (>or=10 IU/L) when compared to pre-booster. Ten years post-primary vaccination, 559 of the 652 initially randomized subjects (86%) were eligible for analysis. Group Y5, 5 years post-booster results: 99% of subjects had detectable levels of antibodies and 96% a titer >or=10 IU/L. The anti-HBs GMTs decreased from 114,489 IU/L one month post-booster to 3354 IU/L 5 years later. Group Y10 results: 10 years post-primary vaccination 96% of subjects had a detectable level of anti-HBs and 85% were above the threshold of 10 IU/L. The GMTs one month post-booster were 31,030 IU/L. The challenge with a booster demonstrated an anamnestic response in 99% of subjects in group Y5 and 100% of subjects in group Y10. All subjects were anti-HBc negative. The booster doses were well tolerated. The excellent anamnestic response observed after the booster dose demonstrates the persistence of immunity in virtually all young adults vaccinated at the age of 8-10 with three paediatric doses of Engerix-B.

Bats in the bedroom, bats in the belfry: reanalysis of the rationale for rabies postexposure prophylaxis.

BACKGROUND: We assessed the scientific basis and practical implications of recommendations made since the late 1990s to offer rabies postexposure prophylaxis (RPEP) for occult bat encounters, including recommendations to offer RPEP to persons with bedroom exposure to a bat while sleeping without evidence of direct physical contact. METHODS: The number needed to treat after bedroom exposure to a bat was calculated as the percentage of population exposed multiplied by the inverse of crude rabies incidence. Bedroom exposure was estimated in a population survey of 14,453 households. Incidence was based on reported human cases in Canada and the United States, 1990-2007. RESULTS: In the population surveyed, bedroom bat exposure while sleeping and without known physical contact occurred at an annual rate of 0.099%. We estimate that <5% of eligible persons with bedroom exposure receive RPEP as recommended. The incidence of human rabies due to bedroom bat exposure without recognized contact was 1 case per 2.7 billion person-years. The number needed to treat to prevent a single case of human rabies in that context ranges from 314,000 to 2.7 million persons. A total of 293-2500 health care professionals working full-time for a full year would be required to prevent a single human case of bat rabies due to bedroom exposure without recognized contact. Amounts of Can $228 million to Can $2.0 billion are additionally required for associated material costs. CONCLUSIONS: Human rabies acquired through bedroom exposure to a bat while sleeping and without recognized contact is rare. Conversely, such exposures are not uncommon in the population, and the resources required for associated RPEP are orders of magnitude higher than those required for most interventions that are considered to be reasonable. Current RPEP recommendations related to occult bat contact should be reconsidered.

Cervical cancer prevention by vaccination: nurses' knowledge, attitudes and intentions.

AIM: This paper is a report of a survey: (1) to document nurses' knowledge, attitudes and information needs regarding human papillomavirus prevention and (2) to determine factors associated with their willingness to recommend human papillomavirus vaccines. BACKGROUND: Persistent infection with human papillomavirus has been causally linked to cervical cancer. Two human papillomavirus vaccines have recently been approved for use in more than 65 countries. Nurses' level of support for the prevention of human papillomavirus related diseases by vaccination has not been researched. METHODS: A survey was conducted in 2007. Self-administered questionnaires were mailed to 1799 randomly selected nurses. Descriptive statistics were generated for all variables. Multivariable logistic regression models were estimated to determine variables associated with the willingness to recommend human papillomavirus vaccines. RESULTS: A total of 946 questionnaires were analyzed and showed that: 97% of nurses perceived routinely recommended vaccines as very useful; 93% would support human papillomavirus vaccination if it is publicly funded; 85% would recommend human papillomavirus vaccines to their patients; 33%, 46% and 61% expect the vaccination to permit screening to begin later in life, reduction of the frequency of screening, and reduction of the number of postscreening interventions, respectively. Respondents' knowledge score was 3.8 out of 7. Several modifiable factors, including knowledge, perceived self-efficacy, and societal and colleagues support were associated with willingness to recommend vaccines. CONCLUSION: Most nurses' support human papillomavirus vaccination, but their active involvement should not be taken for granted. Targeted educational efforts are needed to ensure nurses' involvement in the prevention of human papillomavirus-related diseases.

The cost of preventing rabies at any cost: post-exposure prophylaxis for occult bat contact.

Investigations conducted by public health in Quebec, Canada, following report of human exposure to a bat were reviewed to evaluate the implementation of the recommendation for rabies post-exposure prophylaxis (RPEP) for household bat exposure (without documented direct contact). Of all RPEP recommended, 12% was for direct bat contact with bite, 7% for direct bat contact without known bite and 81% for household exposure. When bat was not available for testing, RPEP was almost always recommended. Household bat exposure has become the most frequent reason for RPEP administration. Given the rarity of rabies, RPEP recommendations related to household bat exposure may warrant review.

Setting priorities for new vaccination programs by using public health officers and immunization managers opinions.

The objective of this work was to assess the opinions of public health professionals (PHPs) about routinely recommended and new vaccines, and to evaluate the feasibility of using a modified Basic Priority Rating System (BPRS) approach to prioritize new immunization programs. One hundred and thirty six PHPs were invited to participate in the survey and 101 responded. Ninty-eight percent of respondents agreed that "recommended vaccines are very useful" (mean score=9.5 out of 10). Between 47% and 100% of respondents agreed with statements about usefulness, safety, effectiveness and acceptability of seven new vaccines (mean scores 5.7-9.7). The highest BPRS scores were observed for MMRV (7.3), DTaP-IPV-HBV-Hib (7.0), and conjugate ACYW-135 (5.4), followed by HPV (4.8), HAV (4.4), rotavirus (1.6) and zoster vaccine (1.5%). The results demonstrate that PHPs perceive presently recommended vaccines as very useful tools in infection prevention. On the other hand, the perceived usefulness, safety, effectiveness, and acceptability of new vaccines are heterogeneous. This heterogeneity is indicative of the complexity of decision-making around implementation of new immunization programs and the need for tools facilitating program prioritization. The modified BPRS approach using survey responses to five statements on program usefulness, vaccine safety, effectiveness, and acceptance by vaccinators and the population is a simple, feasible and inexpensive method of prioritizing new immunization programs. The method we propose is flexible in choosing target groups and allows a large number of professionals to be involved in the decision-making process about new immunization programs.

Protecting the next generation: what is the role of the duration of human papillomavirus vaccine-related immunity?

BACKGROUND: There is strong evidence that human papillomavirus (HPV) is necessary for the development of cervical cancer. A prophylactic HPV vaccine with high reported efficacy was approved in North America in 2006. METHODS: A mathematical model of HPV transmission dynamics was used to simulate different scenarios of natural disease outcomes and intervention strategies. A sensitivity analysis was performed to compensate for uncertainties surrounding key epidemiological parameters. RESULTS: The expected impact that HPV vaccines have on cervical cancer incidence and HPV prevalence in the province of British Columbia in Canada revealed that, for lifelong vaccine-related protection, an immunization routine targeting younger females (grade 6), combined with a 3-year program for adolescent females (grade 9), is the most effective strategy. If vaccine-related protection continues for <10 years, then the targeting of adolescent females would be more beneficial than the targeting of younger females. The incremental benefit if boys, as well as girls, are vaccinated is small. CONCLUSIONS: Optimization of the design of immunization strategies for treatment of HPV depends substantially on the duration of vaccine-induced immunity. Given the uncertainty in estimating this duration, it may be prudent to assume a value close to the lower limit reported and adjust the program when more-accurate information for the length of vaccine-induced immunity becomes available.

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.

Human papilloma virus vaccine and cervical cancer screening acceptability among adults in Quebec, Canada.

BACKGROUND: The Pap test has been used for cervical cancer screening for more than four decades. A human papillomavirus (HPV) vaccine has been approved for use in Canada and is commercially available now. These two preventive interventions should be considered simultaneously. General population support is an important factor for the successful combination of these interventions. The study had two objectives: 1) To assess practices, beliefs, and attitudes regarding Pap test screening and HPV immunization; 2) To identify socio-demographic factors for Pap screening and vaccine acceptability. METHODS: In 2006, 500 adults were invited to participate in a telephone survey in the region of Quebec City (urban and rural population, 600 000), Canada. Some neutral and standardized information on Pap test and HPV was provided before soliciting opinions. RESULTS: 471 adults (18-69 year-olds) answered the questionnaire, the mean age was 45 years, 67% were female, and 65% had college or university degree. Eighty-six percent of women had undergone at least one Pap-test in their life, 55% in the last year, and 15% from 1 to 3 years ago. Among screened women, the test had been performed in the last three years in 100% of 18-30 year-olds, but only in 67% of 60-69 year-olds (P < 0.0001). Only 15% of respondents had heard of HPV. Eighty-seven percent agreed that HPV vaccines could prevent cervical cancer, 73% that the vaccine has to be administered before the onset of sexual activity, 89% would recommend vaccination to their daughters and nieces. Among respondents < 25 years, 91% would agree to receive the vaccine if it is publicly funded, but only 72% would agree to pay $100/dose. CONCLUSION: There is an important heterogeneity in cervical cancer screening frequency and coverage. Despite low awareness of HPV infection, the majority of respondents would recommend or are ready to receive the HPV vaccine, but the cost could prevent its acceptability.

Vaccination against human papillomavirus: a baseline survey of Canadian clinicians' knowledge, attitudes and beliefs.

We assessed Canadian obstetrician/gynaecologists', family physicians' and paediatricians' knowledge, attitudes, and beliefs about HPV infection and prevention, as well as factors associated with willingness to prescribe HPV vaccines. A self-administered, anonymous questionnaire was mailed to 2500 physicians. The participation rate was 51%. Overall, 95% of respondents indicated that the vaccine should be given to girls before the onset of sexual activity; 80% of respondents felt that the best age for an HPV vaccination program is <14 years; 88% of respondents intend to recommend HPV vaccines if they are publicly funded. Several predisposing, reinforcing, organizational, preventive activity and situational factors were independently associated with the intention to prescribe the HPV vaccines. Most physicians expect an important benefit from HPV vaccination and intend to prescribe HPV vaccines (86.7%). To achieve high rates of vaccination coverage, several modifiable factors should be taken in consideration during immunization program implementation.

Trends of hepatitis A hospitalization and risk factors in Quebec, Canada, between 1990 and 2003.

BACKGROUND: In Canada, targeted vaccination of at risk groups for hepatitis A (HA) is done since the mid 1990s resulting in declining incidence. This study estimated the year and age specific hospitalization rates and distribution of risk factors for HA in Quebec, Canada, between 1990 and 2003. METHODS: Records of patients hospitalized with HA-related diagnostic codes were retrieved from the provincial database. Hospital charts of all deceased cases and a random sample of all other records were reviewed. RESULTS: From 1503 hospitalization records, 573 charts were reviewed including 49 (91%) of the 54 deceased patients. Confirmed acute HA was present in 79% of records where HA was the primary diagnosis, and in 3%-8% of records where HA was a secondary diagnosis. From the total estimated number of hospitalizations, 96% had HA as the primary diagnosis. The hospitalization rate decreased from 1.06 per 100 000 person-years between 1990 and 1997 to 0.36 between 1998 and 2003. During the study period, 54% HA hospitalizations were in 20-39 year-olds. The overall case fatality ratio among hospitalized patients was 1.4%, increasing from 0.4% in those < 40 years old to 12.5% in those > or =60 years. By decreasing order, reported risk factors were travel to HA endemic countries (30%), MSM (18%) and household contacts (11%). CONCLUSION: HA hospitalization rates have been low since 1998 but the cause of this is unclear given the cyclical pattern of HA. Travel to endemic countries remains the most important risk factor and improved control of HA will require better strategies to vaccinate travelers.

The challenges facing Canadian trialists in an increasingly competitive global market: What can be done to remain competitive?

Globally, the pharmaceutical industry is condensing into fewer, larger international corporations. This has occurred with the vaccine industry in Canada, where two domestic producers have been absorbed by international companies. This changes the relationship between Canadian vaccine researchers and corporate head office research directors, who carefully assign prelicensure studies to potential market countries around the globe. To succeed in attracting prelicensure vaccine studies, Canadian researchers need to be outstanding in quality, reliability and efficiency. The present article highlights strategies to help researchers remain internationally competitive for industry-sponsored pharmaceutical studies.

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.

Cohort effects in dynamic models and their impact on vaccination programmes: an example from hepatitis A.

BACKGROUND: Infection rates for many infectious diseases have declined over the past century. This has created a cohort effect, whereby older individuals experienced a higher infection rate in their past than younger individuals do now. As a result, age-stratified seroprevalence profiles often differ from what would be expected from constant infection rates. METHODS: Here, we account for the cohort effect by fitting an age-structured compartmental model with declining transmission rates to Hepatitis A seroprevalence data for Canadian-born individuals. We compare the predicted impact of universal vaccination with and without including the cohort effect in the dynamic model. RESULTS: We find that Hepatitis A transmissibility has declined by a factor of 2.8 since the early twentieth century. When the cohort effect is not included in the model, incidence and mortality both with and without vaccination are significantly over-predicted. Incidence (respectively mortality) over a 20 year period of universal vaccination is 34% (respectively 90%) higher than if the cohort effect is included. The percentage reduction in incidence and mortality due to vaccination are also over-predicted when the cohort effect is not included. Similar effects are likely for many other infectious diseases where infection rates have declined significantly over past decades and where immunity is lifelong. CONCLUSION: Failure to account for cohort effects has implications for interpreting seroprevalence data and predicting the impact of vaccination programmes with dynamic models. Cohort effects should be included in dynamic modelling studies whenever applicable.

Comparison of trip characteristics of children and adults with travel-acquired hepatitis A infection.

We compared the trip characteristics of 84 child and 99 adult cases with travel-acquired hepatitis A (HA). Most pediatric cases had traveled in Asia for more than 30 days and had stayed and eaten most of their meals in the homes of friends and relatives in a country where they had not been born. In contrast, the adults with travel-acquired HA had visited Latin America or the Caribbean for 14 days or less and had stayed primarily in hotels. Specific public health interventions should be undertaken to prevent HA in traveling children.

Chapter 22: Assuring the quality, safety and efficacy of HPV vaccines: the scientific basis of regulatory expectations pre- and post-licensure.

The potential of human papillomavirus (HPV) vaccines will only be realized if the vaccine candidates under development prove to be safe and effective and can be consistently produced to define quality standards. Whilst the responsibility for delivering a safe and effective product rests with the vaccine producer, a vaccine requires a license to allow it to be placed on the market. Licensure is based on an evaluation of the safety and efficacy profile of a vaccine candidate by national regulatory authorities, ideally on the basis of internationally agreed, science-based specifications and procedures. For vaccines, these international specifications are developed by the World Health Organization (WHO). The scientific basis for the regulatory evaluation of the safety and efficacy of HPV vaccines is described in this paper. Once a vaccine is licensed, a second set of criteria are evaluated by a different group of experts to provide advice to national health policy decision makers as to whether the vaccine should be introduced into national immunization programmes. Factors, such as evidence of high disease burden and high cost-effectiveness are taken into account in this second decision-making process.

Solicited adverse events after influenza immunization among infants, toddlers, and their household contacts.

OBJECTIVES: We assessed adverse events, including oculorespiratory syndrome, following influenza immunization during the first year of a publicly-funded program for infants, toddlers and their household members in Canada. METHODS: Parents bringing infants and toddlers for influenza immunization to clinics in Quebec or British Columbia consented to structured telephone interview 5 to 10 days later. One adult provided information for all household members. Symptom experience commencing before and after immunization was assessed. Non-immunized persons also served as a comparison group for immunized household members. RESULTS: Sample included 690 immunized infants and toddlers and 1801 household members, 1374 immunized. Only fussiness, fever, decreased appetite, drowsiness, and nasal congestion/coryza were reported for >5% of infants/ toddlers within 72 hours of immunization, but only arm discomfort was reported among >5% of immunized household contacts. In multivariate analysis, muscle ache was the only systemic symptom reported more often by immunized household members compared to non-immunized persons. Oculorespiratory symptoms were infrequent and there was no difference between immunized and non-immunized household members in their report. Less than 1% of adults required time off work because of adverse events following influenza immunization in the household. Less than 2% of subjects experiencing an adverse event following influenza immunization were considered unlikely to be vaccinated again. CONCLUSION: Influenza vaccine is well-tolerated by infants, toddlers and their household members. Post-marketing observational designs are an expedient way to assess adverse events following influenza immunization. These methods should be established and rehearsed annually in preparation for a pandemic.