[Extension of HPV vaccination to boys: Survey of families and general practitioners]. / Extension de la vaccination contre les HPV aux garçons : enquête auprès de familles et de médecins généralistes.

INTRODUCTION: As part of an analysis on the extension of the HPV vaccination to French boys, the French National Cancer Institute (INCa) and the French National Authority for Health (HAS) have conducted in collaboration a survey on HPV vaccine acceptance in July 2019. This survey was completed by parents of children aged 11-19 and general practitioners (GPs). Questions focused on their representations, practices and intentions in the context of the future policy change allowing boys to get vaccinated against HPV. METHODS: The survey was conducted between June 20 and July 12, 2019. It focused on two populations: a nationally representative sample of parents with at least one girl aged 11-19 and/or one boy aged 11-14 (n=1984) and a representative sample of GPs in mainland France. Data were collected through a web-based questionnaire with a mean completion time of 10minutes for parents and GPs. The quota method was applied to ensure the representative nature of the samples based on (i) gender, age, children (girl aged 11-14 and/or boy aged 11-14) of the household, socio-professional category of the "head of the household", size of urban area and region for the parents' sample and based on (ii) gender, age, region and type of practice for the GPs' sample. RESULTS: Although most GPs were very favourable towards HPV vaccination (94%), they considered it one of the most challenging vaccinations to get parents to adhere to (82%). A notable percentage of parents have unfavourable opinions towards HPV vaccination (25%). The three main barriers cited by parents of non-vaccinated girls were: the fear of adverse effects, the lack of information, and the fact that the GP did not propose it. Regarding the extension of HPV vaccination to boys, 84 % of GPs would recommend this vaccination to boys if it was included in the vaccination schedule, and 88 % of those who did not routinely recommend HPV vaccination to girls would be more likely to offer it to girls if the extension was recommended.

Health and economic impact of seasonal influenza mass vaccination strategies in European settings: A mathematical modelling and cost-effectiveness analysis.

INTRODUCTION: Despite seasonal influenza vaccination programmes in most countries targeting individuals aged ≥ 65 (or ≥ 55) years and high risk-groups, significant disease burden remains. We explored the impact and cost-effectiveness of 27 vaccination programmes targeting the elderly and/or children in eight European settings (n = 205.8 million). METHODS: We used an age-structured dynamic-transmission model to infer age- and (sub-)type-specific seasonal influenza virus infections calibrated to England, France, Ireland, Navarra, The Netherlands, Portugal, Scotland, and Spain between 2010/11 and 2017/18. The base-case vaccination scenario consisted of non-adjuvanted, non-high dose trivalent vaccines (TV) and no universal paediatric vaccination. We explored i) moving the elderly to "improved" (i.e., adjuvanted or high-dose) trivalent vaccines (iTV) or non-adjuvanted non-high-dose quadrivalent vaccines (QV); ii) adopting mass paediatric vaccination with TV or QV; and iii) combining the elderly and paediatric strategies. We estimated setting-specific costs and quality-adjusted life years (QALYs) gained from the healthcare perspective, and discounted QALYs at 3.0%. RESULTS: In the elderly, the estimated numbers of infection per 100,000 population are reduced by a median of 261.5 (range across settings: 154.4, 475.7) when moving the elderly to iTV and by 150.8 (77.6, 262.3) when moving them to QV. Through indirect protection, adopting mass paediatric programmes with 25% uptake achieves similar reductions in the elderly of 233.6 using TV (range: 58.9, 425.6) or 266.5 using QV (65.7, 477.9), with substantial health gains from averted infections across ages. At €35,000/QALY gained, moving the elderly to iTV plus adopting mass paediatric QV programmes provides the highest mean net benefits and probabilities of being cost-effective in all settings and paediatric coverage levels. CONCLUSION: Given the direct and indirect protection, and depending on the vaccine prices, model results support a combination of having moved the elderly to an improved vaccine and adopting universal paediatric vaccination programmes across the European settings.

Estimates for quality of life loss due to Respiratory Syncytial Virus.

BACKGROUND: In children aged <5 years in whom severe respiratory syncytial virus (RSV) episodes predominantly occur, there are currently no appropriate standardised instruments to estimate quality of life years (QALY) loss. OBJECTIVES: We estimated the age-specific QALY loss due to RSV by developing a regression model which predicts the QALY loss without the use of standardised instruments. METHODS: We conducted a surveillance study which targeted confirmed RSV episodes in children aged <5 years (confirmed cases) and their household members who experienced symptoms of RSV during the same time (suspected cases). All participants were asked to complete questions regarding their health during the infection, with the suspected cases additionally providing health-related quality of life (HR-QoL) loss estimates by completing EQ-5D-3L-Y or EQ-5D-3L instruments. We used the responses from the suspected cases to calibrate a regression model which estimates the HR-QoL and QALY loss due to infection. FINDINGS: For confirmed RSV cases in children under 5 years of age who sought health care, our model predicted a QALY loss per RSV episode of 3.823 × 10-3 (95% CI 0.492-12.766 × 10-3 ), compared with 3.024 × 10-3 (95% CI 0.329-10.098 × 10-3 ) for under fives who did not seek health care. Quality of life years loss per episode was less for older children and adults, estimated as 1.950 × 10-3 (0.185-9.578 × 10-3 ) and 1.543 × 10-3 (0.136-6.406 × 10-3 ) for those who seek or do not seek health care, respectively. CONCLUSION: Evaluations of potential RSV vaccination programmes should consider their impact across the whole population, not just young child children.

Assessing optimal use of the standard dose adjuvanted trivalent seasonal influenza vaccine in the elderly.

BACKGROUND: Despite a long-standing vaccination programme, seasonal influenza remains a major public health problem in England, in particular for the elderly where a significant disease burden remains despite vaccine coverage approaching the WHO target of 75%. The recently licensed adjuvanted trivalent vaccines (TIV-ADJ) have been shown to offer greater protection for the elderly compared to the standard-dose non-adjuvanted trivalent vaccines (TIV), particularly for those individuals 75 years old and above for whom the TIV has limited effectiveness. We assessed the cost-effectiveness of the TIV-ADJ for use in the elderly. METHODS: We used a dynamic SEIR-type transmission model coupled with an economic evaluation framework, estimating the reduction in GP consultations, hospitalisations and influenza-attributable mortality. We assessed the optimal use of the TIV-ADJ by estimating the cost-effectiveness of programmes that used this vaccine in the 65+ and 75+ age groups. FINDINGS: The use of TIV-ADJ is highly cost-effective for both target age cohorts with incremental cost-effectiveness ratios well below the £20,000 per quality-adjusted life year (QALY) with over 90% probability that the vaccine is cost-effective at a cost-effectiveness threshold of £30,000 per QALY. INTERPRETATION: The increased protection provided across all three influenza vaccine sub-types makes TIV-ADJ a more attractive option than TIV from the perspective of the healthcare provider, driven by the increased efficacy against A(H3N2). When deciding on the optimal use of the newly available vaccine it is important to consider the fact that TIV has very limited effectiveness for the 75+ age group, who would therefore get the greatest benefit from a more effective vaccine. FUNDING: I-MOVE+ project (Integrated Monitoring of Vaccines in Europe) through the European Union's Horizon 2020 research and innovation programme under grant agreement #634446 and the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Respiratory Infections at Imperial College London in partnership with Public Health England, as well as the NIHR HPRU in Immunisation at the London School of Hygiene and Tropical Medicine.

Elucidating the impact of the pneumococcal conjugate vaccine programme on pneumonia, sepsis and otitis media hospital admissions in England using a composite control.

BACKGROUND: The seven-valent pneumococcal conjugate vaccine (PCV) was introduced in England in September 2006, changing to the 13-valent vaccine in April 2010. PCV impact on invasive pneumococcal disease (IPD) has been extensively reported, but less described is its impact on the burden of pneumonia, sepsis and otitis media in the hospital. METHODS: Using details on all admissions to hospitals in England, we compared the incidence of pneumococcal-specific and syndromic disease endpoints in a 24-month pre-PCV period beginning April 2004 to the 24-month period ending March 2015 to derive incidence rate ratios (IRRs). To adjust for possible secular trends in admission practice, IRRs were compared to the IRRs for five control conditions over the same period and the relative change assessed using the geometric mean of the five control IRRs as a composite, and individually for each control condition to give the min-max range. Relative changes were also compared with IRRs for IPD from the national laboratory database. The effect of stratifying cases into those with and without clinical risk factors for pneumococcal infection was explored. RESULTS: Relative reductions in pneumococcal pneumonia were seen in all age groups and in those with and without risk factors; in children under 15 years old reductions were similar in magnitude to reductions in IPD. For pneumonia of unspecified cause, relative reductions were seen in those under 15 years old (maximum reduction in children under 2 years of 34%, min-max: 11-49%) with a relative increase in 65+ year olds most marked in those with underlying risk conditions (41%, min-max: 0-82%). Reductions in pneumococcal sepsis were seen in all age groups, with the largest reduction in children younger than 2 years (67%, min-max 56-75%). Reductions in empyema and lung abscess were also seen in under 15 year olds. Results for other disease endpoints were varied. For disease endpoints showing an increase in raw IRR, the increase was generally reduced when expressed as a relative change. CONCLUSIONS: Use of a composite control and stratification by risk group status can help elucidate the impact of PCV on non-IPD disease endpoints and in vulnerable population groups. We estimate a substantial reduction in the hospitalised burden of pneumococcal pneumonia in all age groups and pneumonia of unspecified cause, empyema and lung abscess in children under 15 years of age since PCV introduction. The increase in unspecified pneumonia in high-risk 65+ year olds may in part reflect their greater susceptibility to develop pneumonia from less pathogenic serotypes that are replacing vaccine types in the nasopharynx.

Impact and cost-effectiveness of different vaccination strategies to reduce the burden of pneumococcal disease among elderly in the Netherlands.

BACKGROUND: Streptococcus pneumoniae causes morbidity and mortality among all ages in The Netherlands. To reduce this burden, infants in The Netherlands receive the 10-valent pneumococcal conjugated vaccine (PCV10), but older persons are not targeted. We assessed the impact and cost-effectiveness of vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV23) or 13-valent PCV (PCV13) among all those aged 60, 65 or 70 and/or in combination with replacing PCV10 with PCV13 in the infant vaccination programme. METHODS: A static cost-effectiveness model was parameterized including projected trends for invasive pneumococcal disease (IPD) and hospitalised community acquired pneumonia (CAP). The different strategies were evaluated using vaccine list prices and a 10-year time horizon. Incremental cost-effectiveness ratios (ICER) were calculated with the current strategy (infant vaccination program with PCV10) as reference. RESULTS: Compared to the reference, the largest impact on pneumococcal disease burden was projected with a combined use of PCV13 among infants and PPV23 at 60, 65 and 70 years, preventing 1,635 cases of IPD and 914 cases of CAP. The most cost-effective strategy was vaccinating with PPV23 at 70 years only with similar low ICERs at age 60 and 65. The impact of the use of PCV13 among infants depends strongly on the projected herd-immunity effect on serotype 19A. Vaccinating elderly with either PCV13 or PPV23 was dominated by PPV23 in all investigated scenarios, mainly due to the lower price of PPV23. CONCLUSION: Under the current assumptions, the best value for money is the use of PPV23 for elderly, with a single dose or at five year increment between age 60 to age 70.

fluEvidenceSynthesis: An R package for evidence synthesis based analysis of epidemiological outbreaks.

Public health related decisions often have to balance the cost of intervention strategies with the benefit of the reduction in disease burden. While the cost can often be inferred, forward modelling of the effect of different intervention options is complicated and disease specific. Here we introduce a package that is aimed to simplify this process. The package allows one to infer parameters using a Bayesian approach, perform forward modelling of the likely results of the proposed intervention and finally perform cost effectiveness analysis of the results. The package is based on a method previously used in the United Kingdom to inform vaccination strategies for influenza, with extensions to make it easily adaptable to other diseases and data sources.

Cost-effectiveness analysis of quadrivalent seasonal influenza vaccines in England.

BACKGROUND: As part of the national seasonal influenza vaccination programme in England and Wales, children receive a quadrivalent vaccine offering protection against two influenza A strains and two influenza B strains. Healthy children receive a quadrivalent live attenuated influenza vaccine (QLAIV), whilst children with contraindications receive the quadrivalent inactivated influenza vaccine (QIIV). Individuals aged younger than 65 years in the clinical risk populations and elderly individuals aged 65+ years receive either a trivalent inactivated influenza vaccine (TIIV) offering protection from two A strains and one B strain or the QIIV at the choice of their general practitioner. The cost-effectiveness of quadrivalent vaccine programmes is an open question. The original analysis that supported the paediatric programme only considered a trivalent live attenuated vaccine (LAIV). The cost-effectiveness of the QIIV to other patients has not been established. We sought to estimate the cost-effectiveness of these programmes, establishing a maximum incremental total cost per dose of quadrivalent vaccines over trivalent vaccines. METHODS: We used the same mathematical model as the analysis that recommended the introduction of the paediatric influenza vaccination programme. The incremental cost of the quadrivalent vaccine is the additional cost over that of the existing trivalent vaccine currently in use. RESULTS: Introducing quadrivalent vaccines can be cost-effective for all targeted groups. However, the cost-effectiveness of the programme is dependent on the choice of target cohort and the cost of the vaccines: the paediatric programme is cost-effective with an increased cost of £6.36 per dose, though an extension to clinical risk individuals younger than 65 years old and further to all elderly individuals means the maximum incremental cost is £1.84 and £0.20 per dose respectively. CONCLUSIONS: Quadrivalent influenza vaccines will bring substantial health benefits, as they are cost-effective in particular target groups.

Social and Economic Impacts of School Influenza Outbreaks in England: Survey of Caregivers.

BACKGROUND: Influenza is a cause of considerable morbidity in England, particularly among children. A total of 39% of all influenza-attributable general practitioner consultations and 37% of all influenza-attributable hospital admissions occur in those aged under 15 years. Few studies have quantified the impact of influenza outbreaks on families. We assessed this impact during 2 influenza seasons. METHODS: We used questionnaires to obtain data in primary schools that reported an outbreak of an influenza-like-illness (ILI). We sought data on the loss of productivity, costs borne by families and loss in health-related quality of life (HRQoL). ILIs were identified using the symptoms criteria from the European Centre for Disease Prevention and Control and the UK Flusurvey. RESULTS: For each child reporting ILI, mean school absence was 3.8 days (95% confidence interval [CI]): 3.0-4.8) with mean work absence for caregivers reported as 3.7 days (95% CI: 2.7-4.8). The mean loss in HRQoL was 2.1 quality-adjusted life days (95% CI: 1.5-2.7). The estimated total pediatric burden of disease for reported school-based outbreaks during the 2 influenza seasons was 105.3 QALYs (95% CI: 77.7-139.0). CONCLUSIONS: This study shows the potential social and economic benefit of vaccination of children during mild influenza seasons.

The economic cost of measles: Healthcare, public health and societal costs of the 2012-13 outbreak in Merseyside, UK.

BACKGROUND: Measles is a highly contagious vaccine-preventable infection that caused large outbreaks in England in 2012 and 2013 in areas which failed to achieve herd protection levels (95%) consistently. We sought to quantify the economic costs associated with the 2012-13 Merseyside measles outbreak, relative to the cost of extending preventative vaccination to secure herd protection. METHODS: A costing model based on a critical literature review was developed. A workshop and interviews were held with key stakeholders in the Merseyside outbreak to understand the pathway of a measles case and then quantify healthcare activity and costs for the main NHS providers and public health team incurred during the initial four month period to May 2012. These data were used to model the total costs of the full outbreak to August 2013, comprising those to healthcare providers for patient treatment, public health and societal productivity losses. The modelled total cost of the full outbreak was compared to the cost of extending the preventative vaccination programme to achieve herd protection. FINDINGS: The Merseyside outbreak included 2458 reported cases. The estimated cost of the outbreak was £ 4.4m (sensitivity analysis £ 3.9 m to £ 5.2m) comprising 15% (£ 0.7 m) NHS patient treatment costs, 40% (£ 1.8m) public health costs and 44% (£ 2.0m) for societal productivity losses. In comparison, over the previous five years in Cheshire and Merseyside a further 11,793 MMR vaccinations would have been needed to achieve herd protection at an estimated cost of £ 182,909 (4% of the total cost of the measles outbreak). INTERPRETATION: Failure to consistently reach MMR uptake levels of 95% across all localities and sectors (achieve herd protection) risks comparatively higher economic costs associated with the containment (including healthcare costs) and implementation of effective public health management of outbreaks. FUNDING: Commissioned by the Cheshire and Merseyside Public Health England Centre.

Targeted vaccination in healthy school children - Can primary school vaccination alone control influenza?

BACKGROUND: The UK commenced an extension to the seasonal influenza vaccination policy in autumn 2014 that will eventually see all healthy children between the ages of 2-16 years offered annual influenza vaccination. Models suggest that the new policy will be both highly effective at reducing the burden of influenza as well as cost-effective. We explore whether targeting vaccination at either primary or secondary schools would be more effective and/or cost-effective than the current strategy. METHODS: An age-structured deterministic transmission dynamic SEIR-type mathematical model was used to simulate a national influenza outbreak in England. Costs including GP consultations, hospitalisations due to influenza and vaccinations were compared to potential gains in quality-adjusted life years achieved through vaccinating healthy children. Costs and benefits of the new JCVI vaccination policy were estimated over a single season, and compared to the hypothesised new policies of targeted and heterogeneous vaccination. FINDINGS AND CONCLUSION: All potential vaccination policies were highly cost-effective. Influenza transmission can be eliminated for a particular season by vaccinating both primary and secondary school children, but not by vaccinating only one group. The most cost-effective policy overall is heterogeneous vaccination coverage with 48% uptake in primary schools and 34% in secondary schools. The Joint Committee on Vaccination and Immunisation can consider a modification to their policy of offering seasonal influenza vaccinations to all healthy children of ages 2-16 years.

Measuring Health Utilities in Children and Adolescents: A Systematic Review of the Literature.

BACKGROUND: The objective of this review was to evaluate the use of all direct and indirect methods used to estimate health utilities in both children and adolescents. Utilities measured pre- and post-intervention are combined with the time over which health states are experienced to calculate quality-adjusted life years (QALYs). Cost-utility analyses (CUAs) estimate the cost-effectiveness of health technologies based on their costs and benefits using QALYs as a measure of benefit. The accurate measurement of QALYs is dependent on using appropriate methods to elicit health utilities. OBJECTIVE: We sought studies that measured health utilities directly from patients or their proxies. We did not exclude those studies that also included adults in the analysis, but excluded those studies focused only on adults. METHODS AND FINDINGS: We evaluated 90 studies from a total of 1,780 selected from the databases. 47 (52%) studies were CUAs incorporated into randomised clinical trials; 23 (26%) were health-state utility assessments; 8 (9%) validated methods and 12 (13%) compared existing or new methods. 22 unique direct or indirect calculation methods were used a total of 137 times. Direct calculation through standard gamble, time trade-off and visual analogue scale was used 32 times. The EuroQol EQ-5D was the most frequently-used single method, selected for 41 studies. 15 of the methods used were generic methods and the remaining 7 were disease-specific. 48 of the 90 studies (53%) used some form of proxy, with 26 (29%) using proxies exclusively to estimate health utilities. CONCLUSIONS: Several child- and adolescent-specific methods are still being developed and validated, leaving many studies using methods that have not been designed or validated for use in children or adolescents. Several studies failed to justify using proxy respondents rather than administering the methods directly to the patients. Only two studies examined missing responses to the methods administered with respect to the patients' ages.

The effect of measles on health-related quality of life: a patient-based survey.

BACKGROUND: Measles is a highly contagious and potentially fatal illness preventable through vaccination. Outbreaks in the UK and many other European countries have been increasing over recent years, with over 3,207 laboratory-confirmed cases reported by Public Health England from January 2012 to the end of June 2013. To aid rational decision making regarding measles control versus other use of healthcare resources, it is important to measure the severity of measles in units that are comparable to other diseases. The standard metric for this in the UK is the quality-adjust life year (QALY). To our knowledge, the impact of measles on health-related quality of life (HRQoL) in terms of QALYs has not been quantified. METHODS AND FINDINGS: Individuals with confirmed measles were sent questionnaires requesting information on the short-term impact of the illness on their HRQoL using the EuroQol EQ-5D-3L questionnaire. HRQoL was reported for the day the questionnaire was received, the worst day of infection and at follow-up three weeks later. 507 questionnaires were sent to individuals with confirmed measles with 203 returned (40%). The majority of respondents were not vaccinated. The mean time off work or school was 9.6 days. The mean duration of perceived illness was 13.8 days. The mean number of QALYs lost was 0.019 (equivalent to 6.9 days). The overall burden of disease in terms of QALYs lost in England based on the total number of confirmed cases in the twelve month period from 1st June 2012 was estimated to be 44.2 QALYs. CONCLUSION: The short-term impact of measles infection on HRQoL is substantial, both at the level of the individual patient and in terms of the overall disease burden. This is the first attempt to quantify QALY-loss due to measles at a population level, and provides important parameters to guide future intervention and control measures.