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.

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.

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.

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.

Booster vaccination of adults with reduced-antigen-content diphtheria, Tetanus and pertussis vaccine: immunogenicity 5 years post-vaccination.

At 60 months post-vaccination, adults (mean age 45.6 years) randomised to receive combined reduced-antigen-content diphtheria-tetanus and acellular pertussis vaccine (dTpa) versus tetanus-diphtheria (Td)+monovalent acellular pertussis (pa) were seroprotected against diphtheria (> or =0.016IU/mL Vero cell assay) and tetanus (> or =0.1IU/mL ELISA assay) in 94.4% and 96.2%, respectively (dTpa), compared with 93.7% and 90.6% (Td+pa). Anti-FHA, anti-PT and anti-PRN antibodies (> or =5EL.U/mL) were maintained in 100%, 89.5% and 95.0% of dTpa versus 100%, 85.5% and 90.6% of pa vaccine recipients. At 5 years post boosting, antibody levels to diphtheria and tetanus are similar amongst adults receiving a dTpa or dT, and pertussis antibodies remain above pre-booster levels in at least 85%.

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.

Varicella vaccination in Australia and New Zealand.

Varicella-zoster virus has been responsible for a significant disease burden, including hospitalizations and deaths in Australia and New Zealand. Varicella vaccine has been available in Australia since 1999 and, since November 2005, has been funded under the National Immunisation Program for use in all children as a single dose at 18 months of age and in a school-based catch-up program at 10-13 years of age. Recent hospitalization data from Australia show a decline in varicella hospitalizations in children 1-4 years of age, most likely related to vaccination. In New Zealand, varicella vaccine has been available since 1999 but is currently not recommended or funded on the New Zealand national immunization schedule. The anticipated licensure of combination measles-mumps-rubella-varicella vaccines in both countries may lead to future schedule changes.

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.

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.

Epidemiology of severe hepatitis A in Indigenous Australian children.

AIMS: To describe the epidemiology of hepatitis A in Indigenous Australian children. METHODS: Analysis and mapping of national notification and hospitalisation data. RESULTS: Indigenous Australian children are at far higher risk of clinical hepatitis A than their non-Indigenous counterparts, particularly in the age group 0-4 years. Rates of hospitalisation (15.5 vs. 0.3 per 100,000) and notification (24.4 vs. 1.8 per 100,000) were higher in Indigenous children aged 0-4 years compared with other children in the same age group. In the age group 5-14 years, the rates were 4.4 per 100,000 (Indigenous) versus 0.6 per 100,000 (non-Indigenous) hospitalisations. This excess morbidity falls sharply with age. Rates were the highest in the Northern Territory, South Australia, Western Australia and North Queensland. CONCLUSIONS: Indigenous children are at risk of hepatitis A, particularly early in life. Mapping shows that rates were the highest in jurisdictions with the largest Indigenous populations. This study presents baseline data against which to measure the success of new hepatitis A vaccination programme for Indigenous Australian children which commenced in 2005.

Risk factors for statin-associated rhabdomyolysis.

PURPOSE: To identify and characterize risk factors for rhabdomyolysis in patients prescribed statin monotherapy or statin plus fibrate therapy. METHODS: A nested case-control study was conducted within a cohort of 252,460 new users of lipid-lowering medications across 11 geographically dispersed U.S. health plans. Twenty-one cases of rhabdomyolysis confirmed by medical record review were compared to 200 individually matched controls without rhabdomyolysis. A conditional logistic regression model was applied to evaluate the effects of age, gender, comorbidities, concurrent medication use, dosage, and duration of statin use on the development of rhabdomyolysis. RESULTS: Statin users 65 years of age and older have four times the risk of hospitalization for rhabdomyolysis than those under age 65 (odds ratio (OR) = 4.36, 95% confidence interval (CI): 1.5,14.1). We also observed a joint effect of high statin dosage and renal disease (p = 0.022). When these two variables were added to the model with age, we obtained an OR of 5.73 for dosage (95%CI: 0.63, 52.6) and 6.26 for renal disease (95%CI: 0.46, 63.38). Although not statistically significant, we did observe a greater than twofold increase in risk for rhabdomyolysis among females (OR = 2.53, 95%CI: 0.91, 7.32). CONCLUSIONS: Findings of this study indicate that older age is a risk factor for rhabdomyolysis among statin users. Although the evidence is not as strong, high statin dosage, renal disease, and female gender may be additional risk factors. Patients at higher risk of developing rhabdomyolysis should be closely monitored for signs and symptoms of the disease.

What maintains parental support for vaccination when challenged by anti-vaccination messages? A qualitative study.

This study sought to explore how parents respond to competing media messages about vaccine safety. Six focus groups with mothers of infants were shown television vignettes of typical pro- and anti-vaccination claims. Thematic analysis of transcripts was undertaken. Mothers expressed surprise and concern about alleged vaccine risks but quickly reinstated their support for vaccination by deference to authority figures; type-casting immunisation opponents; and notions of anticipatory regret, good parenting and social responsibility. We conclude that personal experiences, value systems and level of trust in health professionals are fundamental to parental decision making about vaccination. Vaccination advocacy should increase the focus on matters of process such as maintaining trust and public confidence, particularly in health professionals. Stories about people affected by vaccine-preventable diseases need to re-enter the public discourse.

New-onset and idiopathic thrombotic thrombocytopenic purpura: incidence, diagnostic validity, and potential risk factors.

OBJECTIVE: The aim of this study was to determine the incidence rate for new-onset and idiopathic thrombotic thrombocytopenic purpura (TTP) among adults 20-64 years old, the validity of diagnostic criteria, and potential risk factors for TTP. METHODS: This retrospective observational study analyzed automated administrative data from 11 geographically dispersed U.S. health plans. Cases of TTP were identified based on the presence of an inpatient hospital claim for TTP (ICD-9-CM 446.6) between 1/1/97 and 12/31/01 and confirmed by medical record review. Pharmacy and medical claims were used to evaluate outpatient drug exposure and comorbidities preceding hospitalization for TTP. Cases and the base population were screened so as to result in an incidence rate for idiopathic TTP. RESULTS: We confirmed new-onset and idiopathic TTP in 9 of 15 presumptive cases for an incidence density of 1.4 per million person-years (95% CI: 0.6-2.6). The rate increased to 1.8 per million person-years after projection and age-standardization. The highest incidence rate of TTP was found in patients 50-64 years old (2.8 per million person-years; 95% CI: 0.8-7.1). These 9 patients had no apparent risk factors for TTP based on claims and medical record data. CONCLUSIONS: In a general U.S. population, the incidence rate of confirmed new-onset and idiopathic TTP was lower than previously reported, but appears to be on the rise. Our findings suggest that administrative claims data are useful for identifying outpatient drug exposures and comorbidities potentially associated with TTP.

The MMR vaccination and autism controversy in United Kingdom 1998-2005: inevitable community outrage or a failure of risk communication?

BACKGROUND: The report of an hypothesised link between measles-mumps-rubella (MMR) vaccination and autism in 1998 became a major public health issue in the United Kingdom (UK), leaving most experts surprised by the overwhelming influence it had on public opinion about MMR vaccination. Coverage rates fell dramatically, and did not start to recover until 2004. Could this public reaction have been predicted? METHODS: We used Sandman's model of components predicting community outrage to assess the MMR controversy. RESULTS: The controversy fulfilled all of Sandman's 12 primary components and six of the eight additional components. CONCLUSIONS: The Sandman model provided a useful framework to analyse this controversy and explained a significant portion of the community reaction and subsequent fall in vaccination coverage rates.