Alessia Melegaro

Antibody Responses to Nasopharyngeal Carriage of Streptococcus pneumoniae in Adults: A Longitudinal Household Study

BACKGROUND Natural immunity to Streptococcus pneumoniae is thought to be induced by exposure to S. pneumoniae or cross-reactive antigens. No longitudinal studies of carriage of and immune responses to S. pneumoniae have been conducted using sophisticated immunological laboratory techniques. METHODS We enrolled 121 families with young children into this study. Nasopharyngeal (NP) swabs were collected monthly for 10 months from all family members and were cultured in a standard fashion. Cultured S. pneumoniae isolates were serotyped. At the beginning (month 0) and end (month 10) of the study, venous blood was collected from family members >18 years old. Serotype-specific antipolysaccharide immunoglobulin G (IgG) and functional antibody and antibodies to pneumolysin, pneumococcal surface protein A (PspA), and pneumococcal surface antigen A (PsaA) were measured in paired serum samples. RESULTS Levels of anticapsular IgG increased significantly after carriage of serotypes 9V, 14, 18C, 19F, and 23F by an individual or family member. For serotype 14, a higher level of anticapsular IgG at the beginning of the study was associated with reduced odds of carriage (P = .006). There was a small (approximately 20%) but significant increase in titers of antibodies to PsaA and pneumolysin but no change in titers of antibody to PspA. CONCLUSIONS Adults respond to NP carriage by mounting anticapsular and weak antiprotein antibody responses, and naturally induced anticapsular IgG can prevent carriage.

The 23-Valent Pneumococcal Polysaccharide Vaccine. Part I. Efficacy of PPV in the Elderly: A Comparison of Meta-Analyses

A 23-valent polysaccharide pneumococcal vaccine (PPV) has been available in the UK for more than 20 years and is currently recommended for use in high-risk groups (HRG) of 2+ years of age. The degree of protection afforded by the PPV remains a critical issue, although a number of randomised clinical trials and case–control studies (CCS) have been published. The aim of this work is to review the estimates on the efficacy of PPV against pneumococcal pneumonia and invasive pneumococcal disease (IPD) in the elderly and to perform a meta-analysis in order to obtain a pooled estimate of the level of protection in high and low risk individuals. These two groups of individuals are at the centre of the current debate on whether or not to extend the vaccination programme to all elderly individuals 65+. Only randomised and quasi-randomised studies are included in the analysis and results are compared with previous meta-analyses. The effect of the inclusion of observational studies is investigated in the sensitivity analysis. When taken with the results of other meta-analyses and observational studies, it appears that PPV offers protection against IPD in the general elderly population (VE = 65%; 95% CI:−49–92%) whereas it has a moderate effect in the high-risk elderly (VE = 20%; 95% CI:−188–78%). The vaccine has little or no effect against pneumonia (VE = 16% in the general elderly and −20% in HRG).

A longitudinal household study of Streptococcus pneumoniae nasopharyngeal carriage in a UK setting

A 10-month longitudinal household study of pre-school children and their families was undertaken with monthly visits collecting epidemiological data and nasopharyngeal swabs in Hertfordshire, England from 2001 to 2002. Pneumococcal culture was with standard methods. In total, 121 families (489 individuals) took part. Mean prevalence of carriage ranged from 52% for age groups 0-2 years, 45% for 3-4 years, 21% for 5-17 years and 8% for >or=18 years. Carriage occurred more than once in 86% of children aged 0-2 years compared to 36% of those aged >or=18 years. The most prevalent serotypes in the 0-2 years age group were 6B followed by 19F, 23F, 6A and 14. Young children were responsible for the majority of introductions of new serotypes into a household. Erythromycin resistance (alone or in combination) occurred in 10% of samples and penicillin non-susceptibility in 3.7%. Overall the recently licensed 7-valent conjugate vaccine (PCV) would protect against 64% of serotypes with no intra-serogroup cross protection and 82% with such protection. Nasopharyngeal carriage of S. pneumoniae is common in a UK setting in the pre-conjugate vaccine era. PCV would protect against a large proportion of carriage isolates. However, the impact of vaccination on non-vaccine serotypes will need to be monitored.

Estimating the cost-effectiveness of vaccination against herpes zoster in England and Wales.

A live-attenuated vaccine against herpes zoster (HZ) has been approved for use, on the basis of a large-scale clinical trial that suggests that the vaccine is safe and efficacious. This study uses a Markov cohort model to estimate whether routine vaccination of the elderly (60+) would be cost-effective, when compared with other uses of health care resources. Vaccine efficacy parameters are estimated by fitting a model to clinical trial data. Estimates of QALY losses due to acute HZ and post-herpetic neuralgia were derived by fitting models to data on the duration of pain by severity and the QoL detriment associated with different severity categories, as reported in a number of different studies. Other parameters (such as cost and incidence estimates) were based on the literature, or UK data sources. The results suggest that vaccination of 65 year olds is likely to be cost-effective (base-case ICER=pound20,400 per QALY gained). If the vaccine does offer additional protection against either the severity of disease or the likelihood of developing PHN (as suggested by the clinical trial), then vaccination of all elderly age groups is highly likely to be deemed cost-effective. Vaccination at either 65 or 70 years (depending on assumptions of the vaccine action) is most cost-effective. Including a booster dose at a later age is unlikely to be cost-effective.

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.

Modelling the impact of a combined varicella and zoster vaccination programme on the epidemiology of varicella zoster virus in England

This study updates previous work on modelling the incidence of varicella and Herpes Zoster (HZ) following the introduction of childhood vaccination. The updated model includes new data on age-specific contact patterns, as well as data on the efficacy of zoster vaccination in the elderly and allows for HZ among vaccinees. The current study also looks at two-dose varicella childhood programmes, and assesses the combined impact of varicella vaccination in childhood and zoster vaccination of the elderly. The results suggest that a two-dose schedule is likely to reduce the incidence of varicella to very low levels, provided first dose coverage is around 90% and second dose coverage is in excess of 70%. Single dose varicella vaccination programmes are expected to result in large numbers of breakthrough cases. Childhood vaccination is expected to increase the incidence of zoster for more than 40 years after introduction of the programme, the magnitude of this increase being influenced primarily by the duration of boosting following exposure to the varicella zoster virus. Though this increase in zoster incidence can be partly offset by vaccination of the elderly, the effectiveness of this combined strategy is limited, as much of the increase occurs in those adults too young to be vaccinated. Childhood vaccination at intermediate levels of coverage (70% and 60% for first and second dose coverage respectively) is expected to lead to an increase in adult varicella. At high coverage (90% and 80% coverage) this is unlikely to be the case. These results will be used to inform a cost-effectiveness analysis of combined varicella and zoster vaccination programmes.

The potential cost-effectiveness of acellular pertussis booster vaccination in England and Wales

A cost-effectiveness analysis of the introduction of acellular pertussis booster doses at either 4 or 15 years of age was performed. A transmission dynamic model was used to predict the level of indirect protection in those too young to be vaccinated. Multivariate sensitivity analyses were performed. In England and Wales there are an estimated 35,000 general practitioner (GP) consultations, 5500 inpatient days, and nine deaths annually attributable to pertussis, despite high levels of coverage for the primary course (approximately 95%). Around 80% of the bed-days and 90% of the deaths occur in those too young to be immunised (< 3 months of age). The introduction of acellular booster doses at 4 years is expected to reduce morbidity and mortality in the younger age groups by 40-100%, and at 15 years by 0-100%. From the perspective of the health care provider, roughly 50% of the simulations result in a cost per life-year gained of less than 10,000 pounds for vaccination at 4 years, the corresponding proportion for vaccination at 15 years being only 35%. Apart from the degree of indirect protection the model was most sensitive to the discount rate, the price of the vaccine, and the mortality rate. Significant uncertainty remains regarding the epidemiology of pertussis and the impact of booster doses. Nevertheless, the introduction of acellular boosters, particularly at 4 years, has the potential to be cost-effective in the UK.

Dynamic models of pneumococcal carriage and the impact of the Heptavalent Pneumococcal Conjugate Vaccine on invasive pneumococcal disease

BackgroundThe 7-valent pneumococcal conjugate vaccine has been introduced in national immunisation programmes of most industrialised countries and recently in two African GAVI eligible countries (Rwanda and The Gambia). However the long term effects of PCV are still unclear, as beneficial direct and herd immunity effects might be countered by serotype replacement.MethodA dynamic, age-structured, compartmental model of Streptococcus pneumoniae transmission was developed to predict the potential impact of PCV7 on the incidence of invasive disease accounting for both herd immunity and serotype replacement effects. The model was parameterised using epidemiological data from England and Wales and pre and post-vaccination surveillance data from the US.ResultsModel projections showed that serotype replacement plays a crucial role in determining the overall effect of a PCV7 vaccination programme and could reduce, negate or outweigh its beneficial impact. However, using the estimate of the competition parameter derived from the US post-vaccination experience, an infant vaccination programme would prevent 39,000 IPD cases in the 20 years after PCV7 introduction in the UK. Adding a catch-up campaign for under 2 or under 5 year olds would provide a further reduction of 1,200 or 3,300 IPD cases respectively, mostly in the first few years of the programme.ConclusionsThis analysis suggests that a PCV vaccination programme would eradicate vaccine serotypes from circulation. However, the increase in carriage of non-vaccine serotypes, and the consequent increase in invasive disease, could reduce, negate or outweigh the benefit. These results are sensitive to changes in the protective effect of the vaccine, and, most importantly, to the level of competition between vaccine and non-vaccine types. The techniques developed here can be used to assess the introduction of vaccination programmes in developing countries and provide the basis for cost-effectiveness analyses.

What types of contacts are important for the spread of infections? Using contact survey data to explore European mixing patterns

Knowledge of the determinants of infectious disease transmission is a public health priority as it allows the design of optimal control strategies for endemic or emerging infections. We analyse a detailed dataset on contact patterns across five European countries and use available serological profiles for varicella and parvovirus B19 infections to identify the types of contact that may be most relevant for transmission. We show that models informed by contact data fit well the observed serological profiles of both infections. We find that intimate types of contacts explain the pattern of acquisition of serological markers by age better than other types of social contacts. We observe similar patterns in each of the countries analysed, suggesting that there are consistent biological mechanisms at work.

The 23-valent pneumococcal polysaccharide vaccine. Part II. A cost-effectiveness analysis for invasive disease in the elderly in England and Wales.

The 23-valent pneumococcal polysaccharide vaccine (PPV) has been available for a number of years and is recommended for high-risk categories. Relatively immunocompetent elderly people are not included in this group, although their probability of getting invasive pneumococcal infection is high. The objective of this study was to assess whether vaccinating all elderly people over 65 years of age was a cost-effective policy for England and Wales. The analysis was performed comparing the cost and health effects produced by vaccination, to what would have been occurred if vaccination were not introduced. A decision analysis model was used in order to predict health outcomes under different vaccination scenarios. Unit costs were applied to the outcome and the cost per life-year gained was calculated. Sensitivity analysis was performed to allow for uncertain parameters to vary. The current UK recommendation does not appear to be the most cost-effective strategy due to the low level of efficacy of the vaccine in high-risk groups (HRG) and their shorter life expectancy. Routine vaccination of all elderly appears to be more cost-effective. These results are, nevertheless, very much dependent on the uncertainties around vaccine efficacy estimates, which appear to be still present, especially in HRG, and on the number of hospitalisations and deaths attributable to invasive pneumococcal disease (IPD).