The impact of childhood varicella vaccination on the incidence of herpes zoster in the general population: modelling the effect of exogenous and endogenous varicella-zoster virus immunity boosting.

BACKGROUND: A controversy exists about the potential effect of childhood varicella vaccination on Herpes Zoster (HZ) incidence. Mathematical models projected temporary HZ incidence increase after vaccine introduction that was not confirmed by real-world evidence. These models assume that absence of contacts with infected children would prevent exogenous boosting of Varicella-Zoster-Virus (VZV) immunity and they do not include an endogenous VZV immunity-boosting mechanism following asymptomatic VZV reactivation. This study aims to explore the effect of various assumptions on exogenous and endogenous VZV immunity-boosting on HZ incidence in the general population after introduction of routine childhood varicella vaccination. METHODS: An age-structured dynamic transmission model was adapted and fitted to the seroprevalence of varicella in France in absence of vaccination using the empirical contact matrix. A two-dose childhood varicella vaccination schedule was introduced at 12 and 18 months. Vaccine efficacy was assumed at 65%/95% (dose 1/dose 2), and coverage at 90%/80% (dose 1/dose 2). Exogenous boosting intensity was based on assumptions regarding HZ-immunity duration, age-dependent boosting effect, and HZ reactivation rates fitted to observed HZ incidence. Endogenous boosting was the same as pre-vaccination exogenous boosting but constant over time, whilst exogenous boosting depended on the force of infection. Five scenarios were tested with different weightings of exogenous (Exo) - endogenous (Endo) boosting: 100%Exo-0%Endo, 75%Exo-25%Endo, 50%Exo-50%Endo, 25%Exo-75%Endo, 0%Exo-100%Endo. RESULTS: HZ incidence before varicella vaccination, all ages combined, was estimated at 3.96 per 1000 person-years; it decreased by 64% by year 80 post vaccine introduction, for all boosting assumptions. The 100%Exo-0%Endo boosting scenario, predicted an increase in HZ incidence for the first 21 years post vaccine introduction with a maximum increase of 3.7% (4.1/1000) at year 9. However, with 0%Exo-100%Endo boosting scenario an immediate HZ decline was projected. The maximum HZ incidence increases at 10, 3, and 2 years post vaccination were 1.8% (75%Exo-25%Endo), 0.8% (50%Exo-50%Endo) and 0.2% (25%Exo-75%Endo), respectively. CONCLUSIONS: Assuming modest levels of endogenous boosting, the increase in HZ incidence following childhood varicella vaccination was smaller and lasted for a shorter period compared with 100%Exo-0%Endo boosting assumption. Endogenous boosting mechanism could partly explain the divergence between previous HZ-incidence projections and real-world evidence.

Women and vaccinations: From smallpox to the future, a tribute to a partnership benefiting humanity for over 200 years.

Vaccines were first developed in England over 200 years ago and have made a significant positive impact on human society since. Not often realized is the intimate relationship shared between vaccines and women. Women were key to the initial development of vaccines; some were even advocating the concept of protection against infectious disease through prior asymptomatic infection (by variolation) before the publication of the report of the first successful smallpox vaccination in 1798. Since that milestone, women have been important partners in the development of vaccines and advocates for their widespread introduction. Modern vaccine development would not be possible without the altruistic informed consent granted by many women for the participation of themselves or their children in vaccine clinical trials all over the world. Vaccines have rewarded women handsomely in return. Individual women benefit in many ways ranging from safer pregnancies to preventing cancers to attractive, unblemished skin. Some vaccines are even specifically designed to prevent diseases primarily affecting women such as cervical cancer. Vaccines also have offered societal benefits to women. These include better maternal health and fostering an environment more amenable to effective family planning. With these advances, women become more empowered and have access to better economic opportunities. The challenge of meeting the millennium development goals specifically targeted for women will be facilitated by vaccines. A better realization by women of the benefits of this partnership secured over the past 200 years will enable them to reap fully the rewards of the future.

Anaphylaxis following quadrivalent human papillomavirus vaccination.

BACKGROUND: In 2007, Australia implemented the National human papillomavirus (HPV) Vaccination Program, which provides quadrivalent HPV vaccine free to all women aged 12-26 years. Following notification of 7 presumptive cases of anaphylaxis in the state of New South Wales, Australia, we verified cases and compared the incidence of anaphylaxis following HPV vaccination to other vaccines in comparable settings. METHODS: We contacted all patients with suspected anaphylaxis and obtained detailed histories from telephone interviews and a review of medical records. A multidisciplinary team determined whether each suspected case met the standardized Brighton definition. Some participants also received skin-prick allergy testing for common antigens and components of the HPV vaccine. RESULTS: Of 12 suspected cases, 8 were classified as anaphylaxis. Of these, 4 participants had negative skin-prick test results for intradermal Gardasil. From the 269 680 HPV vaccine doses administered in schools, 7 cases of anaphylaxis were identified, which represents an incidence rate of 2.6 per 100 000 doses (95% CI 1.0-5.3 per 100 000). In comparison, the rate of identified anaphylaxis was 0.1 per 100 000 doses (95% CI 0.003-0.7) for conjugated meningococcal C vaccination in a 2003 school-based program. INTERPRETATION: Based on the number of confirmed cases, the estimated rate of anaphylaxis following quadrivalent HPV vaccine was significantly higher than identified in comparable school-based delivery of other vaccines. However, overall rates were very low and managed appropriately with no serious sequelae.

Compulsory vaccination and conscientious or philosophical exemptions: past, present, and future.

Compulsory vaccination has contributed to the success of immunisation programmes in the USA and Australia, yet the benefits from compulsory vaccination are not universally recognised. Some people--experts and the public alike--believe that the benefits of compulsory vaccination are outweighed by the associated ethical problems. A review of vaccination legislation in the UK, Australia, and the USA raises four main points. First, compulsory vaccination may be effective in preventing disease outbreaks, reaching and sustaining high immunisation coverage rates, and expediting the introduction of new vaccines. Second, to be effective, compulsory programmes must have a reliable supply of safe and effective vaccines and most people must be willing to be vaccinated. Third, allowance of exemptions to compulsory vaccination may limit public backlash. Finally, compulsory vaccination may increase the burden on governments to ensure the safety of vaccines. Nevertheless, although compulsory immunisation can be very effective, it might not be acceptable in some countries where high coverage has been achieved through other approaches or efforts, such as in Sweden, Norway, Denmark, the Netherlands, and the UK. These factors should be considered when compulsory vaccinations are being introduced or immunisation laws refined. Lessons learned from compulsory vaccination could be useful to other public-health programmes.

An observational study of cholecystectomy in patients receiving tegaserod.

BACKGROUND: Registrational studies of patients treated with tegaserod for irritable bowel syndrome (IBS) suggest an increased risk for cholecystectomy versus treatment with placebo. OBJECTIVE: To study cholecystectomy rates in association with tegaserod within a large administrative medical claims database. METHODS: Patients were drawn from a large population within the US with commercial medical insurance. The primary analysis consisted of a comparison of the observed incidence rate for cholecystectomy claims among a large cohort of new-to-therapy tegaserod users with an incidence rate published for tegaserod-naive patients classified with IBS within the same insured population. RESULTS: An inception cohort of 7475 individuals with up to 103 weeks of claims history following initiation of therapy with tegaserod was identified. After a follow-up of 3 months (and thus similar to the longest registrational trials), the observed cholecystectomy incidence rate was 340 per 10,000 person-years (95% CI 258, 442). The rate of cholecystectomy was highest in the earliest months of observation following initiation of tegaserod. The observed cholecystecomy incidence rate is 2.9 times higher than an IBS-specific rate of 119 per 10,000 person-years as published for patients so classified within the same insured population. CONCLUSION: Based on a large, inception cohort, we report a strong temporal association between the initiation of tegaserod therapy and an increased rate for cholecystectomy. The effect size at 3 months was similar to the relative risk for cholecystectomy reported in registrational studies comparing tegaserod with placebo. As misclassification of initial diagnosis for patients presenting with biliary colic-like symptoms may occur, precise measurements of tegaserod-related relative risk for cholecystectomy from observational studies are problematic and will require prospective studies.

Indication and use of drug products used to treat attention-deficit/hyperactivity disorder: a cross-sectional study with inference on the likelihood of treatment in adulthood.

INTRODUCTION: Published literature suggests that attention-deficit/hyperactivity disorder (ADHD) affects 4% of adults and that as many as 60% of children with a diagnosis of ADHD will continue to have problems with inattention and impulsivity in adulthood. We analyzed cross-sectional prescription claims data and data from a national survey of office-based physicians for further inference on the likelihood of treatment with ADHD medications into adulthood. METHODS: This study used data from a proprietary, national survey of office-based physicians (the IMS Health National Disease and Therapeutic Index, NDTI) to describe the indication associated with office visits with mention of common stimulant medications and atomoxetine. Enrollment and prescription claims data maintained by a large national health-care company were analyzed for age-specific utilization of these same agents. RESULTS: Data from the NDTI suggest that the vast majority of visits associated with a stimulant medication or atomoxetine was coded with a diagnosis consistent with a mental health condition and not obesity/weight loss. The health plans included in this study processed 222,096 prescriptions for stimulant medications and atomoxetine among 43,175 unique patients aged 1-64 years during the calendar year 2004. Analyses of pharmacy claims data showed a steep increase in use through age 11 (prevalence=70.3 per 1,000 covered lives) followed by a marked decrease and plateau from age 25 through age 64 years (prevalence=5 to 10 per 1,000 covered lives). CONCLUSIONS: On the basis of comparison of the prevalence rate peak of 70 per 1,000 around age 11 years to a plateau of 7 per 1,000 during the early career years, our results are consistent with a prediction that at least one child in 10 placed on an ADHD medication in childhood will receive treatment in to adulthood. The decrease in the prevalence of use of these medications with advancing age as seen in this cross-sectional study may reflect upon several clinical and secular factors.

Varicella vaccination - the global experience.

INTRODUCTION: Varicella, although a frequently benign childhood disease, nevertheless represents a considerable health burden. WHO recommends including varicella vaccines in universal routine vaccination programs, and maintaining coverage >80%. Many countries have successfully introduced varicella vaccination and have benefited from lower disease burden, but many others have not adopted the vaccine. Reasons include cost commitment for a 'mild childhood disease' or concerns that vaccination will shift varicella to older age groups or increase herpes zoster incidence. Areas covered: This literature review summarizes the effectiveness and epidemiological impact of varicella immunization programs. Expert commentary: Varicella vaccines are immunogenic with acceptable safety profiles. One and two dose schedules are highly effective against varicella and large reductions in disease incidence, particularly moderate-severe disease, have been widely reported. There is currently no evidence to suggest that the introduction of varicella vaccination results in a shift of varicella disease burden to older age groups. Although epidemiological studies have shown an increased incidence of herpes zoster since the vaccines were launched, there are many other contributing factors, and indeed, this secular trend was evident before their introduction. In conclusion, varicella vaccination easily fits into existing immunization programs and significantly reduces the often underestimated burden of varicella.

Prevalence and determinants of influenza vaccination in Australians aged 40 years and over--a national survey.

OBJECTIVES: To determine influenza vaccination coverage in 2001 in Australian adults aged > or = 40 years, assess awareness of and attitudes to influenza vaccine, factors associated with vaccination, and estimate uptake of free vaccine provided to those aged > or = 65 years. METHODS: National computer-assisted telephone interview (CATI) survey in October/November 2001. RESULTS: Interviews were completed with 5,266 people aged > or = 65 and 2,415 aged 40-64 years. Thirty per cent of selected households participated. Overall, 67% of respondents believed that the vaccine was somewhat to very effective in preventing influenza. Seventy-eight per cent of those aged > or = 65 years reported influenza vaccination; 89% had received it free. Independent predictors of vaccination were: belief that influenza vaccine is effective in preventing influenza (OR=13.5, 95% CI 10.6-17.2); and the presence of chronic disease (OR=1.6, 95% CI 1.3-2.0). Overall, 24% of those aged 40-64 years were vaccinated; only 34% of those who met any of the criteria for vaccination (medical risk factor, at-risk occupation, or being Aboriginal or Torres Strait Islander) reported vaccination. CONCLUSIONS: Influenza vaccine coverage was high in those aged > or = 65 years, but coverage of those at-risk aged 40-64 years remained suboptimal. Immunisation against influenza was influenced more by beliefs about the vaccine's effectiveness and existing medical risk factors, rather than socio-demographic factors such as gender and income.

Modelling the impact of vaccination on the epidemiology of varicella zoster virus in Australia.

OBJECTIVE: To model the impact of universal varicella vaccination in Australia. METHODS: The results of an Australia-wide serosurvey for varicella zoster virus (VZV) immunity were used to parameterise realistic, age-structured deterministic models (RAS) developed by Brisson and colleagues. We examined the impact of a vaccination program for one-year-olds alone, and with a catch-up campaign for 11-year-olds, on the incidence of varicella and zoster, using Australia's population structure. Morbidity was then determined by calculating the number of hospital in-patient days. RESULTS: Infant vaccination is predicted to reduce the incidence of varicella. However, zoster incidence is expected to increase initially, assuming exposure to varicella boosts immunity to zoster. Accumulated morbidity from both varicella and zoster is predicted to remain above that expected without vaccination for the first 70 years of an infant program (assuming 90% coverage with boosting for 20 years). However, after 70 years the net health savings from vaccination are predicted to increase substantially. CONCLUSIONS AND IMPLICATIONS: Infant vaccination is expected to be a successful long-term commitment to reducing morbidity associated with VZV infection in Australia.

National serosurvey of poliovirus immunity in Australia, 1996-99.

OBJECTIVE: To measure immunity to poliovirus types 1, 2 and 3 in the Australian population. METHODS: Sera were collected opportunistically from laboratories around Australia between 1996 and 1999. A representative sample by age and gender was tested for neutralising antibodies to poliovirus types 1, 2 and 3. A titre of > or = 8 was considered antibody positive and indicative of immunity. RESULTS: Of the 1,813 sera tested, 82% were antibody positive for poliovirus type 1 and 88% were positive for type 2. Immunity to type 3 poliovirus was lower overall (74%) and especially in school-aged children and young adults. For all three poliovirus types, there were more females immune than males and immunity peaked in the 2-4 years age group. The proportion of the population immune to all three types was 59%, and 3% were negative for all three types. CONCLUSIONS AND IMPLICATIONS: This is the first national serosurvey for immunity to poliovirus in Australia. Herd immunity is probably sufficient to prevent generalised outbreaks due to type 1 and 2 poliovirus, but this may not be the case for type 3. However, localised outbreaks of any poliovirus type could still occur following reintroduction unless uniformly high levels of vaccination coverage are maintained. Ongoing serosurveillance is required following the recent change back to inactivated polio vaccine.

Sampling patients within physician practices and health plans: multistage cluster samples in health services research.

OBJECTIVE: To better inform study design decisions when sampling patients within health plans and physician practices with multiple analysis goals. STUDY SETTING: Chronic eye care patients within six health plans across the United States. STUDY DESIGN: We developed a simulation-based approach for designing multistage samples. We created a range of candidate designs, evaluated them with respect to multiple sampling goals, investigated their tradeoffs, and identified the design that is the best compromise among all goals. This approach recognizes that most data collection efforts have multiple competing goals. DATA COLLECTION: We constructed a sample frame from all diabetic patients in six health plans with evidence of chronic eye disease (glaucoma and retinopathy). PRINCIPAL FINDINGS: Simulations of different study designs can uncover efficiency gains as well as inform potential tradeoffs among study goals. Simulations enable us to quantify these efficiency gains and to draw tradeoff curves. CONCLUSIONS: When designing a complex multistage sample it is desirable to explore the tradeoffs between competing sampling goals via simulation. Simulations enable us to investigate a larger number of candidate designs and are therefore likely to identify more efficient designs.

Varicella and varicella vaccination. An update.

BACKGROUND: Although varicella is generally mild in children, it is often more severe in adults and overall is responsible for approximately 2000 hospital admissions each year in Australia. Live attenuated varicella vaccines have been available in Australia since 2000. They are safe and effective. OBJECTIVE: This article discusses the role of varicella vaccination and management of varicella in pregnancy. DISCUSSION: The National Health and Medical Research Council recommends vaccination of all children at the age of 18 months and a catch up program for nonimmune adolescents and adults. The program is not yet funded by the commonwealth government. Varicella vaccine may be used for postexposure prophylaxis and is most effective if given within three days after exposure, but can be used up to five days from exposure. Varicella in pregnancy may cause congenital malformations; the highest risk (2%) being when maternal infection occurs between 13-20 weeks gestation. Offer varicella zoster immunoglobulin to nonimmune pregnant women, neonates and other high risk subjects with significant exposure to varicella or zoster.

Models of strategies for control of rubella and congenital rubella syndrome-a 40 year experience from Australia.

We investigated the impact of vaccination on rubella epidemiology in Australia, using a mathematical model fitted to Australian serosurvey data and incorporating pre-vaccination European estimates of rubella transmissibility. Mass infant measles-mumps-rubella (MMR) vaccination produced a 99% reduction in both rubella and congenital rubella syndrome (CRS) incidence by 2010 compared to the pre-vaccination era (1960-70). The model is consistent with reductions in CRS based on surveillance of congenital hearing impairment. Model simulations suggest that selective schoolgirl vaccination (1971-88) was associated with a 90% reduction in CRS incidence, but only a 1-4% reduction in rubella incidence. Our model predicted that these reductions in rubella were much less vulnerable to reductions in MMR vaccine coverage than for measles. In the future, a less than 15% decrease in MMR vaccine coverage is estimated to have minimal impact before 2060, but a 20% reduction may result in a 7-fold increase in rubella incidence, with the effective reproductive number R rising from 0.28 to 0.78 by 2060. The 99% reduction in both rubella and CRS incidence and low effective reproductive number (R≤0.28) we documented after 2010 are consistent with Australia having achieved rubella elimination.

Congenital and neonatal varicella: impact of the national varicella vaccination programme in Australia.

OBJECTIVE: Routine varicella zoster vaccination for children aged 18 months began in Australia from November 2005. The aim of this study was to compare the current incidence and outcomes of congenital and neonatal varicella in Australia with similarly collected data from 1995 to 1997. METHODS: Active national prospective surveillance was carried out for congenital and neonatal varicella using the Australian Paediatric Surveillance Unit (APSU) for 3.5 years from June 2006. Around 1300 clinicians reported monthly according to predefined case criteria. RESULTS: During the study period the mean monthly return rate of APSU report cards was 93.7%. Two cases of congenital varicella (0.19 per 100 000 live births per annum) and 16 cases of neonatal varicella (2.0 per 100 000 live births per annum) were identified. During 2008 and 2009 no cases of congenital varicella were reported; neonatal varicella rates declined to 0.7 per 100 000 live births per annum, a significant trend (p=0.005) and a reduction of over 85% compared with rates during 1995-1997 (the prevaccination era) and the first year of the current surveillance study. Eleven of 16 neonatal cases followed prenatal maternal infection; seven of the 11 infections were acquired from children, four of whom were living in the same household. Ten (62.5%) infants with neonatal varicella were admitted to hospital, one of whom developed varicella pneumonitis requiring ventilatory support, but none died. Only one infecting contact had been vaccinated. CONCLUSIONS: There has been an apparent reduction of congenital varicella and a significant reduction of neonatal varicella in Australia following the introduction of universal varicella vaccination in 2005.

Antibody persistence six years after two doses of combined hepatitis A and B vaccine.

Persistent immunity to hepatitis A and hepatitis B antibodies six years after vaccination of adolescents (aged 12-15 years) with a combined hepatitis A and B (HAB) vaccine following a 0, 6 month or a 0, 12 month schedule was assessed. Yearly (Year-2-6) serum samples were tested for anti-HAV and anti-HBs using EIA. Subjects with anti-HBs concentrations <10 mIU/mL (14/23) at Year-5 or Year-6, received an additional HBV vaccine dose approximately 12 months after Year-6. Blood samples were collected pre-booster and 1 month post-booster to assess booster response. 240 subjects were vaccinated in the study; at Year-6, data were available from 88 subjects. At that time 84.8% (39/46; 0, 6 month) and 92.9% (39/42; 0, 12 month) of subjects had anti-HBs concentrations > or = 10 mIU/mL. All but one of the 14 boosted subjects responded to the additional HBV vaccine dose with anti-HBs concentrations > or = 100 mIU/mL. All seroconverted subjects who returned at Year-6 were seropositive for anti-HAV. Simplification, reduced number of doses and similar long-term persistence of immunity make the 0, 6 month and 0, 12 month schedule preferable for immunization against HAV/HBV in this population.

Rapid impact of rotavirus vaccination in the United States: implications for Australia.

Australia is in a unique position to assess the impact of two different rotavirus vaccines.