How to Prevent Vaccines Falling Victim to Their Own Success: Intertemporal Dependency of Incidence Levels on Indirect Effects in Economic Reevaluations.

OBJECTIVES: Incremental cost-effectiveness analyses may inform the optimal choice of healthcare interventions. Nevertheless, for many vaccines, benefits fluctuate with incidence levels over time. Reevaluating a vaccine after it has successfully decreased incidences may eventually cause a disease resurgence if switching to a vaccine with lower indirect benefits. Decisions may successively alternate between vaccines alongside repeated rises and falls in incidence and when indirect effects from historic use are ignored. Our suggested proposal aims to prevent suboptimal decision making. METHODS: We used a conceptual model of demand to illustrate alternating decisions between vaccines because of time-varying levels of indirect effects. Similar to the concept of subsidies, we propose internalizing the indirect effects achievable with vaccines. In a case study over 60 years, we simulated a hypothetical 10-year reevaluation of 2 oncogenic human papillomavirus vaccines, of which only 1 protects additionally against anogenital warts. RESULTS: Our case study showed that the vaccine with additional warts protection is initially valued higher than the vaccine without additional warts protection. After 10 years, this differential decreases because of declines in warts incidence, which supports switching to the nonwarts vaccine that causes a warts resurgence eventually. Instead, pricing the indirect effects separately supports continuing with the warts vaccine. CONCLUSIONS: Ignoring how the observed incidences depend on the indirect effects achieved with a particular vaccine may lead to repeated changes in vaccines at successive reevaluations, with unintended resurgences, economic inefficiencies, and eroding vaccine confidence. We propose internalizing indirect effects to prevent vaccines falling victim to their own success.

The potential health and economic value of SARS-CoV-2 vaccination alongside physical distancing in the UK: a transmission model-based future scenario analysis and economic evaluation.

BACKGROUND: In response to the COVID-19 pandemic, the UK first adopted physical distancing measures in March, 2020. Vaccines against SARS-CoV-2 became available in December, 2020. We explored the health and economic value of introducing SARS-CoV-2 immunisation alongside physical distancing in the UK to gain insights about possible future scenarios in a post-vaccination era. METHODS: We used an age-structured dynamic transmission and economic model to explore different scenarios of UK mass immunisation programmes over 10 years. We compared vaccinating 75% of individuals aged 15 years or older (and annually revaccinating 50% of individuals aged 15-64 years and 75% of individuals aged 65 years or older) to no vaccination. We assumed either 50% vaccine efficacy against disease and 45-week protection (worst-case scenario) or 95% vaccine efficacy against infection and 3-year protection (best-case scenario). Natural immunity was assumed to wane within 45 weeks. We also explored the additional impact of physical distancing on vaccination by assuming either an initial lockdown followed by voluntary physical distancing, or an initial lockdown followed by increased physical distancing mandated above a certain threshold of incident daily infections. We considered benefits in terms of quality-adjusted life-years (QALYs) and costs, both to the health-care payer and the national economy. We discounted future costs and QALYs at 3·5% annually and assumed a monetary value per QALY of £20 000 and a conservative long-run cost per vaccine dose of £15. We explored and varied these parameters in sensitivity analyses. We expressed the health and economic benefits of each scenario with the net monetary value: QALYs × (monetary value per QALY) - costs. FINDINGS: Without the initial lockdown, vaccination, and increased physical distancing, we estimated 148·0 million (95% uncertainty interval 48·5-198·8) COVID-19 cases and 3·1 million (0·84-4·5) deaths would occur in the UK over 10 years. In the best-case scenario, vaccination minimises community transmission without future periods of increased physical distancing, whereas SARS-CoV-2 becomes endemic with biannual epidemics in the worst-case scenario. Ongoing transmission is also expected in intermediate scenarios with vaccine efficacy similar to published clinical trial data. From a health-care perspective, introducing vaccination leads to incremental net monetary values ranging from £12·0 billion to £334·7 billion in the best-case scenario and from -£1·1 billion to £56·9 billion in the worst-case scenario. Incremental net monetary values of increased physical distancing might be negative from a societal perspective if national economy losses are persistent and large. INTERPRETATION: Our model findings highlight the substantial health and economic value of introducing SARS-CoV-2 vaccination. Smaller outbreaks could continue even with vaccines, but population-wide implementation of increased physical distancing might no longer be justifiable. Our study provides early insights about possible future post-vaccination scenarios from an economic and epidemiological perspective. FUNDING: National Institute for Health Research, European Commission, Bill & Melinda Gates Foundation.

The impact of COVID-19 control measures on social contacts and transmission in Kenyan informal settlements.

BACKGROUND: Many low- and middle-income countries have implemented control measures against coronavirus disease 2019 (COVID-19). However, it is not clear to what extent these measures explain the low numbers of recorded COVID-19 cases and deaths in Africa. One of the main aims of control measures is to reduce respiratory pathogen transmission through direct contact with others. In this study, we collect contact data from residents of informal settlements around Nairobi, Kenya, to assess if control measures have changed contact patterns, and estimate the impact of changes on the basic reproduction number (R0). METHODS: We conducted a social contact survey with 213 residents of five informal settlements around Nairobi in early May 2020, 4 weeks after the Kenyan government introduced enhanced physical distancing measures and a curfew between 7 pm and 5 am. Respondents were asked to report all direct physical and non-physical contacts made the previous day, alongside a questionnaire asking about the social and economic impact of COVID-19 and control measures. We examined contact patterns by demographic factors, including socioeconomic status. We described the impact of COVID-19 and control measures on income and food security. We compared contact patterns during control measures to patterns from non-pandemic periods to estimate the change in R0. RESULTS: We estimate that control measures reduced physical contacts by 62% and non-physical contacts by either 63% or 67%, depending on the pre-COVID-19 comparison matrix used. Masks were worn by at least one person in 92% of contacts. Respondents in the poorest socioeconomic quintile reported 1.5 times more contacts than those in the richest. Eighty-six percent of respondents reported a total or partial loss of income due to COVID-19, and 74% reported eating less or skipping meals due to having too little money for food. CONCLUSION: COVID-19 control measures have had a large impact on direct contacts and therefore transmission, but have also caused considerable economic and food insecurity. Reductions in R0 are consistent with the comparatively low epidemic growth in Kenya and other sub-Saharan African countries that implemented similar, early control measures. However, negative and inequitable impacts on economic and food security may mean control measures are not sustainable in the longer term.

The impact of Covid-19, associated behaviours and policies on the UK economy: A computable general equilibrium model.

We estimate the potential impact of COVID-19 on the United Kingdom economy, including direct disease effects, preventive public actions and associated policies. A sectoral, whole-economy macroeconomic model was linked to a population-wide epidemiological demographic model to assess the potential macroeconomic impact of COVID-19, together with policies to mitigate or suppress the pandemic by means of home quarantine, school closures, social distancing and accompanying business closures. Our simulations indicate that, assuming a clinical attack rate of 48% and a case fatality ratio of 1.5%, COVID-19 alone would impose a direct health-related economic burden of £39.6bn (1.73% of GDP) on the UK economy. Mitigation strategies imposed for 12 weeks reduce case fatalities by 29%, but the total cost to the economy is £308bn (13.5% of GDP); £66bn (2.9% of GDP) of which is attributable to labour lost from working parents during school closures, and £201bn (8.8% of GDP) of which is attributable to business closures. Suppressing the pandemic over a longer period of time may reduce deaths by 95%, but the total cost to the UK economy also increases to £668bn (29.2% of GDP), where £166bn (7.3% of GDP) is attributable to school closures and 502bn (21.9% of GDP) to business closures. Our analyses suggest Covid-19 has the potential to impose unprecedented economic costs on the UK economy, and whilst public actions are necessary to minimise mortality, the duration of school and business closures are key to determining the economic cost. The initial economic support package promised by the UK government may be proportionate to the costs of mitigating Covid-19, but without alternative measures to reduce the scale and duration of school and business closures, the economic support may be insufficient to compensate for longer term suppression of the pandemic which could generate an even greater health impact through major recession.

Effects of non-pharmaceutical interventions on COVID-19 cases, deaths, and demand for hospital services in the UK: a modelling study.

BACKGROUND: Non-pharmaceutical interventions have been implemented to reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the UK. Projecting the size of an unmitigated epidemic and the potential effect of different control measures has been crucial to support evidence-based policy making during the early stages of the epidemic. This study assesses the potential impact of different control measures for mitigating the burden of COVID-19 in the UK. METHODS: We used a stochastic age-structured transmission model to explore a range of intervention scenarios, tracking 66·4 million people aggregated to 186 county-level administrative units in England, Wales, Scotland, and Northern Ireland. The four base interventions modelled were school closures, physical distancing, shielding of people aged 70 years or older, and self-isolation of symptomatic cases. We also modelled the combination of these interventions, as well as a programme of intensive interventions with phased lockdown-type restrictions that substantially limited contacts outside of the home for repeated periods. We simulated different triggers for the introduction of interventions, and estimated the impact of varying adherence to interventions across counties. For each scenario, we projected estimated new cases over time, patients requiring inpatient and critical care (ie, admission to the intensive care units [ICU]) treatment, and deaths, and compared the effect of each intervention on the basic reproduction number, R0. FINDINGS: We projected a median unmitigated burden of 23 million (95% prediction interval 13-30) clinical cases and 350 000 deaths (170 000-480 000) due to COVID-19 in the UK by December, 2021. We found that the four base interventions were each likely to decrease R0, but not sufficiently to prevent ICU demand from exceeding health service capacity. The combined intervention was more effective at reducing R0, but only lockdown periods were sufficient to bring R0 near or below 1; the most stringent lockdown scenario resulted in a projected 120 000 cases (46 000-700 000) and 50 000 deaths (9300-160 000). Intensive interventions with lockdown periods would need to be in place for a large proportion of the coming year to prevent health-care demand exceeding availability. INTERPRETATION: The characteristics of SARS-CoV-2 mean that extreme measures are probably required to bring the epidemic under control and to prevent very large numbers of deaths and an excess of demand on hospital beds, especially those in ICUs. FUNDING: Medical Research Council.

Quantifying the impact of physical distance measures on the transmission of COVID-19 in the UK.

BACKGROUND: To mitigate and slow the spread of COVID-19, many countries have adopted unprecedented physical distancing policies, including the UK. We evaluate whether these measures might be sufficient to control the epidemic by estimating their impact on the reproduction number (R0, the average number of secondary cases generated per case). METHODS: We asked a representative sample of UK adults about their contact patterns on the previous day. The questionnaire was conducted online via email recruitment and documents the age and location of contacts and a measure of their intimacy (whether physical contact was made or not). In addition, we asked about adherence to different physical distancing measures. The first surveys were sent on Tuesday, 24 March, 1 day after a "lockdown" was implemented across the UK. We compared measured contact patterns during the "lockdown" to patterns of social contact made during a non-epidemic period. By comparing these, we estimated the change in reproduction number as a consequence of the physical distancing measures imposed. We used a meta-analysis of published estimates to inform our estimates of the reproduction number before interventions were put in place. RESULTS: We found a 74% reduction in the average daily number of contacts observed per participant (from 10.8 to 2.8). This would be sufficient to reduce R0 from 2.6 prior to lockdown to 0.62 (95% confidence interval [CI] 0.37-0.89) after the lockdown, based on all types of contact and 0.37 (95% CI = 0.22-0.53) for physical (skin to skin) contacts only. CONCLUSIONS: The physical distancing measures adopted by the UK public have substantially reduced contact levels and will likely lead to a substantial impact and a decline in cases in the coming weeks. However, this projected decline in incidence will not occur immediately as there are significant delays between infection, the onset of symptomatic disease, and hospitalisation, as well as further delays to these events being reported. Tracking behavioural change can give a more rapid assessment of the impact of physical distancing measures than routine epidemiological surveillance.

The cost of insecurity: from flare-up to control of a major Ebola virus disease hotspot during the outbreak in the Democratic Republic of the Congo, 2019.

The ongoing Ebola outbreak in the eastern Democratic Republic of the Congo is facing unprecedented levels of insecurity and violence. We evaluate the likely impact in terms of added transmissibility and cases of major security incidents in the Butembo coordination hub. We also show that despite this additional burden, an adapted response strategy involving enlarged ring vaccination around clusters of cases and enhanced community engagement managed to bring this main hotspot under control.

Estimating the burden of dengue and the impact of release of wMel Wolbachia-infected mosquitoes in Indonesia: a modelling study.

BACKGROUND: Wolbachia-infected mosquitoes reduce dengue virus transmission, and city-wide releases in Yogyakarta city, Indonesia, are showing promising entomological results. Accurate estimates of the burden of dengue, its spatial distribution and the potential impact of Wolbachia are critical in guiding funder and government decisions on its future wider use. METHODS: Here, we combine multiple modelling methods for burden estimation to predict national case burden disaggregated by severity and map the distribution of burden across the country using three separate data sources. An ensemble of transmission models then predicts the estimated reduction in dengue transmission following a nationwide roll-out of wMel Wolbachia. RESULTS: We estimate that 7.8 million (95% uncertainty interval [UI] 1.8-17.7 million) symptomatic dengue cases occurred in Indonesia in 2015 and were associated with 332,865 (UI 94,175-754,203) lost disability-adjusted life years (DALYs). The majority of dengue's burden was due to non-severe cases that did not seek treatment or were challenging to diagnose in outpatient settings leading to substantial underreporting. Estimated burden was highly concentrated in a small number of large cities with 90% of dengue cases occurring in 15.3% of land area. Implementing a nationwide Wolbachia population replacement programme was estimated to avert 86.2% (UI 36.2-99.9%) of cases over a long-term average. CONCLUSIONS: These results suggest interventions targeted to the highest burden cities can have a disproportionate impact on dengue burden. Area-wide interventions, such as Wolbachia, that are deployed based on the area covered could protect people more efficiently than individual-based interventions, such as vaccines, in such dense environments.

Combining serological and contact data to derive target immunity levels for achieving and maintaining measles elimination.

BACKGROUND: Vaccination has reduced the global incidence of measles to the lowest rates in history. However, local interruption of measles virus transmission requires sustained high levels of population immunity that can be challenging to achieve and maintain. The herd immunity threshold for measles is typically stipulated at 90-95%. This figure does not easily translate into age-specific immunity levels required to interrupt transmission. Previous estimates of such levels were based on speculative contact patterns based on historical data from high-income countries. The aim of this study was to determine age-specific immunity levels that would ensure elimination of measles when taking into account empirically observed contact patterns. METHODS: We combined estimated immunity levels from serological data in 17 countries with studies of age-specific mixing patterns to derive contact-adjusted immunity levels. We then compared these to case data from the 10 years following the seroprevalence studies to establish a contact-adjusted immunity threshold for elimination. We lastly combined a range of hypothetical immunity profiles with contact data from a wide range of socioeconomic and demographic settings to determine whether they would be sufficient for elimination. RESULTS: We found that contact-adjusted immunity levels were able to predict whether countries would experience outbreaks in the decade following the serological studies in about 70% of countries. The corresponding threshold level of contact-adjusted immunity was found to be 93%, corresponding to an average basic reproduction number of approximately 14. Testing different scenarios of immunity with this threshold level using contact studies from around the world, we found that 95% immunity would have to be achieved by the age of five and maintained across older age groups to guarantee elimination. This reflects a greater level of immunity required in 5-9-year-olds than established previously. CONCLUSIONS: The immunity levels we found necessary for measles elimination are higher than previous guidance. The importance of achieving high immunity levels in 5-9-year-olds presents both a challenge and an opportunity. While such high levels can be difficult to achieve, school entry provides an opportunity to ensure sufficient vaccination coverage. Combined with observations of contact patterns, further national and sub-national serological studies could serve to highlight key gaps in immunity that need to be filled in order to achieve national and regional measles elimination.

An online decision tree for vaccine efficacy trial design during infectious disease epidemics: The InterVax-Tool.

BACKGROUND: Licensed vaccines are urgently needed for emerging infectious diseases, but the nature of these epidemics causes challenges for the design of phase III trials to evaluate vaccine efficacy. Designing and executing rigorous, fast, and ethical, vaccine efficacy trials is difficult, and the decisions and limitations in the design of these trials encompass epidemiological, logistical, regulatory, statistical, and ethical dimensions. RESULTS: Trial design decisions are complex and interrelated, but current guidance documents do not lend themselves to efficient decision-making. We created InterVax-Tool (http://vaxeval.com), an online, interactive decision-support tool, to help diverse stakeholders navigate the decisions in the design of phase III vaccine trials. InterVax-Tool offers high-level visual and interactive assistance through a set of four decision trees, guiding users through selection of the: (1) Primary Endpoint, (2) Target Population, (3) Randomization Scheme, and, (4) Comparator. We provide guidance on how key considerations - grouped as Epidemiological, Vaccine-related, Infrastructural, or Sociocultural - inform each decision in the trial design process. CONCLUSIONS: InterVax-Tool facilitates structured, transparent, and collaborative discussion of trial design, while recording the decision-making process. Users can save and share their decisions, which is useful both for comparing proposed trial designs, and for justifying particular design choices. Here, we describe the goals and features of InterVax-Tool as well as its application to the design of a Zika vaccine efficacy trial.

Quantifying the impact of social groups and vaccination on inequalities in infectious diseases using a mathematical model.

BACKGROUND: Social and cultural disparities in infectious disease burden are caused by systematic differences between communities. Some differences have a direct and proportional impact on disease burden, such as health-seeking behaviour and severity of infection. Other differences-such as contact rates and susceptibility-affect the risk of transmission, where the impact on disease burden is indirect and remains unclear. Furthermore, the concomitant impact of vaccination on such inequalities is not well understood. METHODS: To quantify the role of differences in transmission on inequalities and the subsequent impact of vaccination, we developed a novel mathematical framework that integrates a mechanistic model of disease transmission with a demographic model of social structure, calibrated to epidemiologic and empirical social contact data. RESULTS: Our model suggests realistic differences in two key factors contributing to the rates of transmission-contact rate and susceptibility-between two social groups can lead to twice the risk of infection in the high-risk population group relative to the low-risk population group. The more isolated the high-risk group, the greater this disease inequality. Vaccination amplified this inequality further: equal vaccine uptake across the two population groups led to up to seven times the risk of infection in the high-risk group. To mitigate these inequalities, the high-risk population group would require disproportionately high vaccination uptake. CONCLUSION: Our results suggest that differences in contact rate and susceptibility can play an important role in explaining observed inequalities in infectious diseases. Importantly, we demonstrate that, contrary to social policy intentions, promoting an equal vaccine uptake across population groups may magnify inequalities in infectious disease risk.

Predicting the impact of pneumococcal conjugate vaccine programme options in Vietnam.

Although catch-up campaigns (CCs) at the introduction of pneumococcal conjugate vaccines (PCVs) may accelerate their impact, supply constraints may limit their benefit if the need for additional PCV doses results in introduction delay. We studied the impact of PCV13 introduction with and without CC in Nha Trang, Vietnam - a country that has not yet introduced PCV - through a dynamic transmission model. We modelled the impact on carriage and invasive pneumococcal disease (IPD) of routine vaccination (RV) only and that of RV with CCs targeting <1y olds (CC1), <2y olds (CC2) and <5y olds (CC5). The model was fitted to nasopharyngeal carriage data, and post-PCV predictions were based on best estimates of parameters governing post-PCV dynamics. With RV only, elimination in carriage of vaccine-type (VT) serotypes is predicted to occur across all age groups within 10 years after introduction, with near-complete replacement by non-VT. Most of the benefit of CCs is predicted to occur within the first 3 years with the highest impact at one year, when IPD incidence is predicted to be 11% (95%CrI 9 - 14%) lower than RV with CC1, 25% (21 - 30 %) lower with CC2 and 38% (32 - 46%) lower with CC5. However, CCs would only prevent more cases of IPD insofar as such campaigns do not delay introduction by more than about 6, 12 and 18 months for CC1, CC2 and CC5. Those findings are important to help guide vaccine introduction in countries that have not yet introduced PCV, particularly in Asia.

Effect of HPV vaccination and cervical cancer screening in England by ethnicity: a modelling study.

BACKGROUND: Health equality is increasingly being considered alongside overall health gain when assessing public health interventions. However, the trade-off between the direct effects of vaccination and herd immunity could lead to unintuitive consequences for the distribution of disease burden within a population. We used a transmission dynamic model of human papillomavirus (HPV) to investigate the effect of ethnic disparities in vaccine and cervical screening uptake on inequality in disease incidence in England. METHODS: We developed an individual-based model of HPV transmission and disease, parameterising it with the latest data for sexual behaviour (from National Survey of Sexual Attitudes and Lifestyles [Natsal-3]) and vaccine and screening uptake by ethnicity (from Public Health England [PHE]) and fitting it to data for HPV prevalence (from ARTISTIC, PHE, Natsal-3) and HPV-related disease incidence (from National Cancer Registry [ONS]). The outcome of interest was the age-adjusted incidence of HPV-related cancer (both cervical and non-cervical) in all women in England in view of differences and changes in vaccination and screening uptake by ethnicity in England, over time. We also studied three potential public health interventions aimed at reducing inequality in HPV-related disease incidence: increasing uptake in black and Asian females to match that in whites for vaccination; cervical screening in women who turn 25 in 2018 or later; and cervical screening in all ages. FINDINGS: In the pre-vaccination era, before 2008, women from ethnic minorities in England reported a disproportionate share of cervical disease. Our model suggests that Asian women were 1·7 times (95% credibility interval [CI] 1·1-2·7) more likely to be diagnosed with cervical cancer than white women (22·8 vs 13·4 cases per 100 000 women). Because HPV vaccination uptake is lower in ethnic minorities, we predict an initial widening of this gap, with cervical cancer incidence in Asian women up to 2·5 times higher (95% CI 1·3-4·8) than in white women 20 years after vaccine introduction (corresponding to an additional 10·8 [95% CI 10·1-11·5] cases every year). In time, we predict that herd immunity benefits will diffuse from the larger white sub-population and the disparity will narrow. Increased cervical screening uptake in vaccinated women from ethnic minorities would lead to rapid improvement in equality with parity in incidence after 20 years of HPV vaccination. INTERPRETATION: Our study suggests that the introduction of HPV vaccination in England will initially widen a pre-existing disparity in the incidence of HPV-related cancer by ethnicity, partly due to herd immunity disproportionately benefiting subgroups with high vaccination rates. Although in time this induced disparity will narrow, increasing cervical screening uptake in girls from ethnic minorities should be encouraged to eliminate the inequality in cervical cancer incidence in the medium term. We recommend that dynamic effects should be considered when estimating the effect of public health programmes on equality. FUNDING: Cancer Research UK.

Estimating the opportunity costs of bed-days.

Opportunity costs of bed-days are fundamental to understanding the value of healthcare systems. They greatly influence burden of disease estimations and economic evaluations involving stays in healthcare facilities. However, different estimation techniques employ assumptions that differ crucially in whether to consider the value of the second-best alternative use forgone, of any available alternative use, or the value of the actually chosen alternative. Informed by economic theory, this paper provides a taxonomic framework of methodologies for estimating the opportunity costs of resources. This taxonomy is then applied to bed-days by classifying existing approaches accordingly. We highlight differences in valuation between approaches and the perspective adopted, and we use our framework to appraise the assumptions and biases underlying the standard approaches that have been widely adopted mostly unquestioned in the past, such as the conventional use of reference costs and administrative accounting data. Drawing on these findings, we present a novel approach for estimating the opportunity costs of bed-days in terms of health forgone for the second-best patient, but expressed monetarily. This alternative approach effectively re-connects to the concept of choice and explicitly considers net benefits. It is broadly applicable across settings and for other resources besides bed-days.

Assessing the efficiency of catch-up campaigns for the introduction of pneumococcal conjugate vaccine: a modelling study based on data from PCV10 introduction in Kilifi, Kenya.

BACKGROUND: The World Health Organisation recommends the use of catch-up campaigns as part of the introduction of pneumococcal conjugate vaccines (PCVs) to accelerate herd protection and hence PCV impact. The value of a catch-up campaign is a trade-off between the costs of vaccinating additional age groups and the benefit of additional direct and indirect protection. There is a paucity of observational data, particularly from low- and middle-income countries, to quantify the optimal breadth of such catch-up campaigns. METHODS: In Kilifi, Kenya, PCV10 was introduced in 2011 using the three-dose Expanded Programme on Immunisation infant schedule and a catch-up campaign in children <5 years old. We fitted a transmission dynamic model to detailed local data, including nasopharyngeal carriage and invasive pneumococcal disease (IPD), to infer the marginal impact of the PCV catch-up campaign over hypothetical routine cohort vaccination in that setting and to estimate the likely impact of alternative campaigns and their dose efficiency. RESULTS: We estimated that, within 10 years of introduction, the catch-up campaign among children <5 years old prevents an additional 65 (48-84) IPD cases across age groups, compared to PCV cohort introduction alone. Vaccination without any catch-up campaign prevented 155 (121-193) IPD cases and used 1321 (1058-1698) PCV doses per IPD case prevented. In the years after implementation, the PCV programme gradually accrues herd protection, and hence its dose efficiency increases: 10 years after the start of cohort vaccination alone the programme used 910 (732-1184) doses per IPD case averted. We estimated that a two-dose catch-up among children <1 year old uses an additional 910 (732-1184) doses per additional IPD case averted. Furthermore, by extending a single-dose catch-up campaign to children aged 1 to <2 years and subsequently to those aged 2 to <5 years, the campaign uses an additional 412 (296-606) and 543 (403-763) doses per additional IPD case averted. These results were not sensitive to vaccine coverage, serotype competition, the duration of vaccine protection or the relative protection of infants. CONCLUSIONS: We find that catch-up campaigns are a highly dose-efficient way to accelerate population protection against pneumococcal disease.

Impact and Cost-effectiveness of Selective Human Papillomavirus Vaccination of Men Who Have Sex With Men.

Background: Men who have sex with men (MSM) have a high lifetime risk of anogenital warts and cancers related to infection with human papillomavirus (HPV). They also benefit less from herd protection than heterosexual males in settings with female-only HPV vaccination. Methods: We evaluated the potential health impact and cost-effectiveness of offering vaccination to MSM who visit genitourinary medicine (GUM) clinics. We used a mathematical model of HPV 6/11/16/18 sexual transmission within an MSM population in England, parameterized with sexual behaviour, GUM attendance, HPV prevalence, HIV prevalence, warts, and cancer incidence data. Interventions considered were offering HPV vaccination to either HIV-positive MSM or MSM regardless of HIV status, for age bands 16-25, 16-30, 16-35, and 16-40 years. Results: Substantial declines in anogenital warts and male HPV-related cancer incidence are projected to occur following an offer of vaccination to MSM. MSM not attending GUM clinics will partially benefit from herd protection. Offering vaccination to HIV-positive MSM up to age 40 is likely to be cost-effective if vaccine procurement and administration costs are below £96.50 a dose. At £48 a dose, offering vaccination to all MSM up to age 40 is likely to be cost-effective. Conclusions: Quadrivalent HPV vaccination of MSM via GUM clinics is likely to be an effective and cost-effective way of reducing the burden of HPV-related disease in MSM.

Cost-effectiveness of Ward Closure to Control Outbreaks of Norovirus Infection in United Kingdom National Health Service Hospitals.

BACKGROUND: Norovirus is the most common cause of outbreaks of acute gastroenteritis in National Health Service hospitals in the United Kingdom. Wards (units) are often closed to new admissions to stop the spread of the virus, but there is limited evidence describing the cost-effectiveness of ward closure. METHODS: An economic analysis based on the results from a large, prospective, active-surveillance study of gastroenteritis outbreaks in hospitals and from an epidemic simulation study compared alternative ward closure options evaluated at different time points since first infection, assuming different efficacies of ward closure. RESULTS: A total of 232 gastroenteritis outbreaks occurring in 14 hospitals over a 1-year period were analyzed. The risk of a new outbreak in a hospital is significantly associated with the number of admission, general medical, and long-stay wards that are concurrently affected but is less affected by the level of community transmission. Ward closure leads to higher costs but reduces the number of new outbreaks by 6%-56% and the number of clinical cases by 1%-55%, depending on the efficacy of the intervention. The incremental cost per outbreak averted varies from £10 000 ($14 000) to £306 000 ($428 000), and the cost per case averted varies from £500 ($700) to £61 000 ($85 000). The cost-effectiveness of ward closure decreases as the efficacy of the intervention increases, and the cost-effectiveness increases with the timing of the intervention. The efficacy of ward closure is critical from a cost-effectiveness perspective. CONCLUSIONS: Ward closure may be cost-effective, particularly if targeted to high-throughput units.

Extending the elderly- and risk-group programme of vaccination against seasonal influenza in England and Wales: a cost-effectiveness study.

BACKGROUND: The present study aims to evaluate the cost-effectiveness of extending the pre-2013 influenza immunisation programme for high-risk and elderly individuals to those at low risk of developing complications following infection with seasonal influenza. METHODS: We performed an economic evaluation comparing different extensions of the pre-2013 influenza programme to seven possible age groups of low-risk individuals (aged 2-4 years, 50-64 years, 5-16 years, 2-4 and 50-64 years, 2-16 years, 2-16 and 50-64 years, and 2-64 years). These extensions are evaluated incrementally on four base scenarios (no vaccination, risk group only with coverage as observed between 1995 and 2009, risk group and 65+, and risk group with 75% coverage and 65+). Impact of vaccination is assessed using a transmission model built and parameterised from a previously published study. The study population is all individuals of all ages in England and Wales representing an average total of 52.6 million people over 14 influenza seasons (1995-2009). RESULTS: The influenza programme (risk group and elderly) prior to 2013 is likely to be cost effective (incremental cost effectiveness ratio: 7,475 £/QALY, net benefit: 253 M£ [15-829]). Extension to any one of the low-risk target groups defined earlier is likely to be cost-effective. However, strategies that do not include vaccination of school-aged children are less likely to be cost-effective. The most efficient strategy is extension to the 5-16 year age group while universal vaccination (extension to all low-risk individuals over 2 years) will achieve the highest net benefit. While extension to the 2-16 year age group is likely to be very cost effective, the cost-effectiveness of extensions beyond 2-16 years is very uncertain. Extension to the 5-16 year age group would likely remain cost-effective even without herd immunity effects to other age groups. As our study includes a strong historical component, our results depend on the efficacy of the influenza vaccine remaining at levels similar to the ones achieved in the past over a long-period of time (assumed to vary between 28% and 70% depending of the circulating strains and age groups). CONCLUSIONS: Making use of surveillance data from over a decade in conjunction with a dynamic model, we find that vaccination of children in the United Kingdom is likely to be highly cost-effective, not only for their own benefit but also to reduce the disease burden in the rest of the community.