Modelling alternative strategies for delivering hepatitis B vaccine in prisons: the impact on the vaccination coverage of the injecting drug user population.

Since 2001 hepatitis B vaccination has been offered to prisoners on reception into prisons in England and Wales. However, short campaigns of vaccinating the entire population of individual prisons have achieved high vaccination coverage for limited periods, suggesting that short campaigns may be a preferable way of vaccinating prisoners. A model is used that describes the flow of prisoners through prisons stratified by injecting status to compare a range of vaccination scenarios that describe vaccination on prison reception or via regular short campaigns. Model results suggest that vaccinating on prison reception can capture a greater proportion of the injecting drug user (IDU) population than the comparable campaign scenarios (63% vs. 55.6% respectively). Vaccination on prison reception is also more efficient at capturing IDUs for vaccination than vaccination via a campaign, although vaccination via campaigns may have a role with some infections for overall control.

Assessing the burden of influenza and other respiratory infections in England and Wales.

OBJECTIVES: To estimate the burden of influenza in England and Wales, in terms of general practice consultations, hospital admissions and deaths. METHODS: Multivariable regression was used to estimate the influenza attributable fraction of general practice consultations recorded in the general practice research database, of hospital admissions from hospital episode statistics and of deaths recorded by the Office of National Statistics. RESULTS: An estimated 779,000 (95%CI+/-258,000)-1,164,000 (95%CI+/-425,000) general practice consultations, 19,000 (95%CI+/-5000)-31,200 (95%CI+/-11,000) hospital admissions and 18,500 (95%CI 2500)-24,800 (95%CI+/-2500) deaths annually are attributable to influenza infections. In primary care, the bulk of the burden falls on those under the age of 45, whereas the elderly are more likely to be hospitalised and to die. CONCLUSIONS: Although there are significant uncertainties, and considerable year on year variations, it is clear that the burden of influenza is considerable. Although much of this burden falls on the elderly, significant numbers of general practice consultations, hospitalisations and even some deaths occur annually in children in England and Wales.

Modelling the force of infection for hepatitis B and hepatitis C in injecting drug users in England and Wales.

BACKGROUND: Injecting drug use is a key risk factor, for several infections of public health importance, especially hepatitis B (HBV) and hepatitis C (HCV). In England and Wales, where less than 1% of the population are likely to be injecting drug users (IDUs), approximately 38% of laboratory reports of HBV, and 95% of HCV reports are attributed to injecting drug use. METHODS: Voluntary unlinked anonymous surveys have been performed on IDUs in contact with specialist agencies throughout England and Wales. Since 1990 more than 20,000 saliva samples from current IDUs have been tested for markers of infection for HBV, HCV testing has been included since 1998. The analysis here considers those IDUs tested for HBV and HCV (n = 5,682) from 1998-2003. This study derives maximum likelihood estimates of the force of infection (the rate at which susceptible IDUs acquire infection) for HBV and HCV in the IDU population and their trends over time and injecting career length. The presence of individual heterogeneity of risk behaviour and background HBV prevalence due to routes of transmission other than injecting are also considered. RESULTS: For both HBV and HCV, IDUs are at greatest risk from infection in their first year of injecting (Forces of infection in new initiates 1999-2003: HBV = 0.1076 95% C.I: 0.0840-0.1327 HCV = 0.1608 95% C.I: 0.1314-0.1942) compared to experienced IDUs (Force of infection in experienced IDUs 1999-2003: HBV = 0.0353 95% C.I: 0.0198-0.0596, HCV = 0.0526 95% C.I: 0.0310-0.0863) although independently of this there is evidence of heterogeneity of risk behaviour with a small number of IDUs at increased risk of infection. No trends in the FOI over time were detected. There was only limited evidence of background HBV infection due to factors other than injecting. CONCLUSION: The models highlight the need to increase interventions that target new initiates to injecting to reduce the transmission of blood-borne viruses. Although from the evidence here, identification of those individuals that engage in heightened at-risk behaviour may also help in planning effective interventions. The data and methods described here may provide a baseline for monitoring the success of public health interventions.

Interpreting serological surveys using mixture models: the seroepidemiology of measles, mumps and rubella in England and Wales at the beginning of the 21st century.

A mixture modelling technique is applied to age-specific frequency distributions of quantitative results from serological surveys for measles, mumps and rubella using samples collected across the age range in England and Wales in 2000. In accordance with previous studies the analysis suggests that the antibody response to natural infection is stronger than that produced by vaccination, that vaccine-induced antibody levels wane with time and that levels of vaccine-induced antibody response vary for each virus infection being strongest for rubella and weakest for mumps. The current mumps epidemic in the United Kingdom is focused in cohorts born during 1982-1987 who were too old to have received routine MMR vaccination. In the cohort born in 1981-1985 the model estimates that 7.5% have no evidence of mumps specific IgG and 24.9% have the lowest level of detectable antibody. The similar proportions of mumps antibody in these categories among cohorts with opportunity for 1 or 2 doses of vaccine is a concern, as the degree to which these individuals are protected is unclear. Investigations into the efficacy of two doses of a mumps containing vaccine should be a priority during the current epidemic.

Modelling the hepatitis B vaccination programme in prisons.

A vaccination programme offering hepatitis B (HBV) vaccine at reception into prison has been introduced into selected prisons in England and Wales. Over the coming years it is anticipated this vaccination programme will be extended. A model has been developed to assess the potential impact of the programme on the vaccination coverage of prisoners, ex-prisoners, and injecting drug users (IDUs). Under a range of coverage scenarios, the model predicts the change over time in the vaccination status of new entrants to prison, current prisoners and IDUs in the community. The model predicts that at baseline in 2012 57% of the IDU population will be vaccinated with up to 72% being vaccinated depending on the vaccination scenario implemented. These results are sensitive to the size of the IDU population in England and Wales and the average time served by an IDU during each prison visit. IDUs that do not receive HBV vaccine in the community are at increased risk from HBV infection. The HBV vaccination programme in prisons is an effective way of vaccinating this hard-to-reach population although vaccination coverage on prison reception must be increased to achieve this.

The natural history of meningococcal carriage and disease.

The prevalence of Neisseria meningitidis carriage is highest in teenagers and lowest in young children. In contrast, invasive meningococcal disease is most common in young children with a smaller secondary peak in teenagers. Data on carriage and disease were analysed to quantify the risks of infection and disease by age and serogroup. The forces of infection for serogroups B, C, other meningococci and Neisseria lactamica were modelled together with the risk of disease given infection for serogroups B and C, using maximum likelihood to fit the models to the available data. The risk of meningococcal disease given infection declines steeply through childhood and is higher for serogroup C than for serogroup B. The secondary peak in disease in teenagers appears to be explained mostly by increased transmission although there is a suggestion that other factors may also contribute. These analyses provide important insights and may be used to guide further data collection and modelling studies.

Modelling the impact of prison vaccination on hepatitis B transmission within the injecting drug user population of England and Wales.

A vaccination programme offering hepatitis B (HBV) vaccine at reception into prison has been introduced into selected prisons in England and Wales. The work here considers the impact of prison vaccination on the incidence and prevalence of hepatitis B virus (HBV) in the injecting drug user (IDU) population of England and Wales. A dynamic model of the transmission of HBV in IDUs is developed with key model assumptions and parameters being subject to sensitivity analyses. The base case model (that assumes that the vaccination coverage on prison reception is 5% in 2002, 10% in 2003 and then increases linearly up to 50% of prison receptions being vaccinated by 2006) predicts that the incidence of HBV in IDUs might be reduced by almost 80% in 12 years, and the HBV prevalence (IDUs ever infected by HBV) may be reduced from approximately 18% in 2002 to 7% in 2015. The model presented here demonstrates that HBV vaccination on prison reception can have a significant impact on the prevalence and incidence of HBV in the IDU population over time.

The seroepidemiology of Bordetella pertussis infection in Western Europe.

High titres of pertussis toxin (PT) antibody have been shown to be predictive of recent infection with Bordetella pertussis. The seroprevalence of standardized anti-PT antibody was determined in six Western European countries between 1994 and 1998 and related to historical surveillance and vaccine programme data. Standardized anti-PT titres were calculated for a series of whole-cell and acellular pertussis vaccine trials. For the serological surveys, high-titre sera (> 125 units/ml) were distributed throughout all age groups in both high- (> 90%) and low-coverage (< 90%) countries. High-titre sera were more likely in infants in countries using high-titre-producing vaccines in their primary programme (Italy, 11.5%; Western Germany, 13.3%; France, 4.3%; Eastern Germany, 4.0%) compared to other countries (The Netherlands, 0.5%; Finland, 0%). Recent infection was significantly more likely in adolescents (10-19 years old) and adults in high-coverage countries (Finland, The Netherlands, France, East Germany), whereas infection was more likely in children (3-9 years old) than adolescents in low-coverage (< 90%; Italy, West Germany, United Kingdom) countries. The impact and role of programmatic changes introduced after these surveys aimed at protecting infants from severe disease by accelerating the primary schedule or vaccinating older children and adolescents with booster doses can be evaluated with this approach.

Estimating the transmission parameters of pneumococcal carriage in households.

This paper analyses Streptococcus pneumoniae transmission dynamics in households using longitudinal data on pneumococcal (Pnc) carriage in the United Kingdom. Ten consecutive swabs were taken at 4-week intervals from all members of 121 households. The family status is derived from the observed Pnc carriage status of each family member. Transition matrices are built for each family size and composition containing the observed frequency of transitions between family statuses over a 28-day interval. A density-dependent transmission model is fitted to derive maximum-likelihood estimates of the duration of carriage and acquisition rates from the community and from infected individuals within the household. Parameter values are estimated for children (< 5 years) and adults (5+ years). The duration of carriage is longer in children < 5 years of age than in older family members (51 vs. 19 days). Children are 3-4 times more likely than adults to acquire Pnc infection from the community. Transmission rates within the household suggest that adults are more infectious but less susceptible than children. Transmission within the household is most important in large families. The proportion of household-acquired infection ranges from 29 to 46% in households of three persons to 38-50% in larger households. Evidence of density-dependent within-household transmission is found, although the strength of this relationship is not clear from the model estimates.

Sero-epidemiology of Bordetella pertussis in England and Wales.

The incidence of pertussis infection can be estimated in the population by defining a single high titre of anti pertussis toxin (PT) immunoglobulin G (IgG) antibody predictive of recent infection. Sera samples collected in 1986, 1996 or annually between 1987 and 1998 were tested for anti-PT IgG antibody. In 1996, the age-adjusted prevalence of pertussis infection was 1.2% and was higher in children than in adults. Amongst samples collected annually, older age and female sex, but none of the temporal variables, were associated with a serologically defined pertussis infection. There is an important incidence of infection in the population, which is greater amongst children than adults, but there is only limited evidence of a correlation with epidemic cycles.

Seroprevalence of antibody to varicella zoster virus in England and Wales in children and young adults.

This is the first large-scale study to investigate the seroprevalence of varicella zoster (VZV) in the general population of England and Wales. The study focused on those aged 1-20 years, that age group in whom most infections occur. Prevalence rose rapidly with age, with 53% of children showing evidence of prior infection by the age of 5 years and most young adults having experienced infection. In addition to using a fixed cut-off recommended by the manufacturer, a mixture modelling technique was also used to define the proportion of the population seropositive in each age group. This was shown to be a more accurate approach to categorizing data from an epidemiological perspective.

Branching process models for surveillance of infectious diseases controlled by mass vaccination.

Mass vaccination programmes aim to maintain the effective reproduction number R of an infection below unity. We describe methods for monitoring the value of R using surveillance data. The models are based on branching processes in which R is identified with the offspring mean. We derive unconditional likelihoods for the offspring mean using data on outbreak size and outbreak duration. We also discuss Bayesian methods, implemented by Metropolis-Hastings sampling. We investigate by simulation the validity of the models with respect to depletion of susceptibles and under-ascertainment of cases. The methods are illustrated using surveillance data on measles in the USA.

The predicted impact of private sector MMR vaccination on the burden of Congenital Rubella Syndrome.

In many developing countries, Measles-Mumps-Rubella (MMR) vaccine is available through the private but not the public sectors, and there is no systematic rubella vaccination among adult women. In this paper, we extend previous modeling studies to demonstrate that in developing countries with a medium-high force of infection (200-400/1000 per year), current levels of private sector MMR coverage (<60%) would lead to increases in the incidence of Congenital Rubella Syndrome (CRS) both among unvaccinated individuals and the general population even when mixing between vaccinated and unvaccinated individuals is fairly minimal. Our findings highlight the need for countries to establish surveillance of trends in susceptibility to rubella and CRS incidence and perhaps introduce rubella vaccination among women of child-bearing age.

Analysis of longitudinal bacterial carriage studies accounting for sensitivity of swabbing: an application to Neisseria meningitidis.

Longitudinal carriage studies of colonizing bacteria such as Neisseria meningitidis can provide important insights into the transmission dynamics of these organisms. Carriage is detected by culturing from a nasopharyngeal swab, but the sensitivity of this technique is low and varies between studies. This paper applies a statistical method for estimating the sensitivity of swabbing, infection rate, recovery rate and initial prevalence of carriage to three longitudinal carriage studies of N. meningitidis. These parameters and 95% confidence intervals were estimated using maximum likelihood techniques. The sensitivity of swabbing was estimated to be 60-83% and this should be taken into account when interpreting carriage studies. The estimates of force of infection and recovery rates seem to be consistent with estimates from more traditional methods. Differences in the parameter estimates between datasets may be due to differences in study design. This method could be used to assist in the design of future carriage studies.

Economic evaluation of options for measles vaccination strategy in a hypothetical Western European country.

In this study an analysis was made of economic costs and medical effects (by cost-effectiveness and cost-benefit analysis) associated with measles vaccination in a hypothetical Western European country. We analysed ten vaccination options in terms of past and future vaccination coverage. We show that several of the proposed strategies for improving measles vaccination coverage are preferable to maintaining the existing policies, regardless of past coverage and the viewpoint of the analysis. For society, very high coverage (95%) two-dose vaccination is most optimal, irrespective of past vaccination coverage. The addition of a one-time campaign (to reduce susceptibility in (pre-)adolescent age groups) to such a high coverage two-dose vaccination programme is cost-saving to the health-care payer and to society when coverage in the past was low (< or = 70%). Even when coverage in the past was high (90%) for more than a decade, this 'maximum strategy' could be implemented at an acceptable cost to the health-care payer (incremental direct costs per discounted life-year gained < 30,000 Euros), and at net savings to society.

Improving sensitivity of oral fluid testing in IgG prevalence studies: application of mixture models to a rubella antibody survey.

A method for the analysis of age-stratified antibody prevalence surveys is applied to a previously reported survey of antibody to rubella virus using oral fluid samples in which the sensitivity of the assay used was shown to be compromised. The age-specific distribution of the quantitative results of antibody tests using oral fluids is modelled as a mixture of strong positive, weak positive and negative components. This yields maximum likelihood estimates of the prevalence at each age and demonstrates that, when used in conjunction with mixture modelling techniques, the results of antibody prevalence studies using oral fluids accurately reflect those obtained using sera.

Evolutionary relationships, but functional differences, between the Drosophila and human Toll-like receptor families.

The Toll receptor was first found to function in the dorsoventral patterning pathway of Drosophila embryos. It is activated by a specific protein ligand, Spätzle, generated at ventral positions in the early embryo. Drosophila Toll (dToll) also functions in innate immune responses to Gram-positive bacteria and fungi, and Spätzle is required for this response. We have shown that Spätzle is necessary and sufficient for activation of the dToll pathway, and that it probably acts by cross-linking two molecules of Toll to form homodimers. In the present paper, we contrast this mode of regulation with that proposed for the vertebrate Toll-like receptor family, which mediate analogous responses to pathogen pattern antigens. In contrast with dToll, these receptors appear to be activated by direct exposure to pathogen patterns, such as peptidoglycan and lipopolysaccharide. We discuss the evolutionary basis of this functional divergence of the vertebrate and invertebrate Toll-like receptors.

Varicella vaccination: impact of vaccine efficacy on the epidemiology of VZV.

In 1995, varicella vaccination was introduced into the infant immunization schedule of the United States. Currently, many other countries are considering mass varicella vaccination. Mass vaccination has two dangers: it could increase the number of varicella cases in adults, where severity is greater, and increase cases of zoster. A deterministic, realistic, age-structured model (RAS) was built to study these concerns. Model parameter estimates were derived from a review of the literature and surveillance data from England and Wales. Different vaccine efficacy scenarios, vaccine coverages, and vaccination strategies were investigated. The model predicts that, although an upward shift in the age at infection occurs, the overall morbidity due to varicella is likely to decrease following mass infant vaccination. On the other hand, cases of zoster may significantly increase in the first 50 years following vaccination. The model predicts that, in a population similar to England and Wales (50 m people), varicella vaccination with 90% coverage would prevent 0.6 m inpatient days due to varicella but would generate an extra 1.1 m inpatient days due to zoster over the first 65 years. Thus, under base-case model assumptions, the gain in reduction of varicella morbidity from infant vaccination is offset in the short-term by the increases in zoster morbidity (using inpatient days as a proxy). Paradoxically, less effective vaccines or vaccine programmes can be more effective in reducing overall morbidity (varicella + zoster) by allowing the virus to circulate more, which produces a smaller shift in the age at infection and a smaller increase in zoster cases.