Conceptual frameworks and key dimensions to support coverage decisions for vaccines

Vaccine 33 (2015) 1206–1217

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Conceptual frameworks and key dimensions to support coverage decisions for vaccines Marien González-Lorenzo a,∗ , Alessandra Piatti c , Liliana Coppola c , Maria Gramegna c , Vittorio Demicheli d , Alessia Melegaro e , Marcello Tirani a , Elena Parmelli f,g , Francesco Auxilia a , Lorenzo Moja a,b , the Vaccine Decision Group1 a

Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Italy Unità di Epidemiologia Clinica, IRCCS Istituto ortopedico Galeazzi, Milano, Italy c Direzione Generale Salute, UO Governo della Prevenzione e Tutela Sanitaria, Regione Lombardia, Milano, Italy d Servizio Regionale di Riferimento per l’Epidemiologia, SSEpi-SeREMI - CochraneVaccines Field, Azienda Sanitaria Locale ASL AL, Alessandria, Italy e Dipartimento di Analisi delle Politiche e Management Pubblico & Centro Dondena per la ricerca sulle Dinamiche Sociali e Politiche Pubbliche, Università Bocconi, Milano, Italy f Dipartimento di Epidemiologia del Servizio Sanitario Regionale del Lazio, Roma, Italy g Centro Cochrane Italiano, Università degli Studi di Modena e Reggio Emilia, Italy b

a r t i c l e

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Article history: Received 29 August 2014 Received in revised form 8 December 2014 Accepted 9 December 2014 Available online 19 December 2014 Keywords: Decision-making Vaccination Decision aid Model Framework Health policy Immunisation programmes

a b s t r a c t Background: Health policy makers often have to face decisions on whether and how to incorporate new vaccines into immunisation plans. This study aims to review and catalogue the relevant current frameworks and taxonomies on vaccines and connect these to the DECIDE Evidence to Decision framework (EtD), a general framework based on evidence-based criteria to guide decision-making on intervention adoption. Methods: We systematically searched MEDLINE, EMBASE, Cochrane Library and funding agency websites from 1990 to 2013. We included systematic reviews and primary studies presenting decision-making tools for community vaccine adoption. We qualitatively summarised the reports by purpose, targeted country, principal results, and decisional models. We then extracted and compared the dimensions adopted by vaccine frameworks across studies. Results: Fourteen studies (five systematic reviews and nine primary studies) were included. Several factors frequently influenced decision-makers’ views on vaccines: the most frequent political-context factors considered were Importance of illness or problem, Vaccine characteristics, Resource use, and Feasibility. Others such as Values and preferences and Acceptability were less consistently reported. We did not find evidence on the reasons why a framework for vaccine adoption differs from that for decisions on the adoption of an intervention in general, such as the EtD. There are limited data on how dimensions are explained in practical factors and directly linked to coverage decisions. Conclusions: This review summarises conceptual models and taxonomy of a heterogeneous and evolving area in health policy decisions. A shared and comprehensive framework on vaccine coverage remains to be achieved with its single dimensions (epidemiologic, effectiveness, economic, and social) valued differently across studies. A generic tool such as the EtD conceptualises all relevant dimensions, and might reduce inconsistencies. © 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/).

∗ Corresponding author at: Dipartimento di Scienze Biomediche per la Salute, Università degli studi di Milano. Via Carlo Pascal 36, Milano 20133, Italy. Tel.: +39 02 50315119. E-mail addresses: [email protected], [email protected] (M. González-Lorenzo). 1 The Vaccine Decision Group: Marien González-Lorenzo ([email protected]), Alessandra Piatti (alessandra [email protected]), Liliana Coppola (liliana [email protected]), Maria Gramegna (Maria [email protected]), Vittorio Demicheli ([email protected]), Alessia Melegaro ([email protected]), Marcello Tirani ([email protected]), Elena Parmelli ([email protected]), Francesco Auxilia ([email protected]), Lorenzo Moja ([email protected]), Vanna Pistotti ([email protected])(IRCCS Istituto di ricerche farmacologiche Mario Negri, Milano, Italy; Network Italiano Cochrane), Alessandro Zanetti ([email protected])(Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Italy). http://dx.doi.org/10.1016/j.vaccine.2014.12.020 0264-410X/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/).

M. González-Lorenzo et al. / Vaccine 33 (2015) 1206–1217

1. Background Over the past decade, several randomised controlled trials evaluating the safety or the efficacy of new vaccines have been completed [1]. One approved by drug regulatory agencies, some of these vaccines, such as those for human papilloma virus and H1N1 influenza A, have been introduced into low, middle, and highincome countries. Health care systems are discussing the potential adoption of other vaccines such as rotavirus, pneumococcal and meningococcal vaccines [2,3]. New vaccines might represent major medical breakthroughs in preventive care, while others may have scarce or limited innovative value. In both cases, the production and commercialisation of newly developed vaccines are likely to be more expansive than previous ones. From a public health perspective, health policy makers will need to answer questions regarding dosage, general effectiveness, safety, impact, and expected compliance of vaccines. They must further make decisions between new vaccines and alternative programmes (e.g., interventions for stopping the spread of infection), weighing the costs and expected health benefits in the development of national immunisation programmes [4]. Limited financial resources should be distributed in a fair and effective manner to achieve the best possible outcomes within local rather than global conditions, considering all direct and indirect consequences of the immunisation programme. In 2005, the World Health Organisation (WHO) released the document entitled “Vaccine introduction guidelines. Adding a vaccine to a national immunisation programme: decision and implementation” [5]. The document has since been updated [6]. This publication offers decision-makers a structured and comprehensive framework for determining the impact of one or more vaccine options, and provides answers to various policy questions. Other frameworks following a similar approach to the WHO have also been proposed (e.g. Global Immunisation Strategic Framework 2011–2015) [7], outlining useful criteria, indicators, sources of data and validation processes. The Developing and Evaluating Communication Strategies to Support Informed Decisions and Practice Based on Evidence (DECIDE) project is a collaborative research project aimed to develop and evaluate communication strategies to support evidence informed decisions building on the work of the Grading of Recommendations Assessment Development and Evaluation (GRADE) Working Group and the Cochrane Applicability and Recommendations Methods Group [8–10]. As a part of the DECIDE project, a general framework for communicating evidence to inform coverage decisions called Evidence to Decision (EtD) for coverage is being developed [9,11]. In this context, “coverage” decision is defined as the potential provision of the intervention (i.e., vaccine) at no cost to the user and at the expense of the regional or national health system, health insurance organisations or health foundations and charities (e.g., the GAVI Alliance). This framework aims to be general, encompassing a wide spectrum of decisions from preventive to therapeutic or diagnostic interventions. The framework is divided into three parts: the first presents the condition and background information; the second involves a table that provides information identified as essential to make a particular type of decision (i.e., dimension and criteria used); the third summarises the components used to make the decision [9]. The aim of our study was to explore specific aspects of health policy decision frameworks on vaccines. We a priori assumed that vaccines differ from other drugs at least in the types of recommendations or decisions involving its uptake by health care systems (e.g., clinical recommendations from an individual patient perspective or from a population perspective. Thus, we thought a generic framework such as the EtD may not be suitable for vaccines. When

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a generic framework is applied to support specific decisions (i.e., vaccines), its validity and sensitivity can be limited. To fully address the issues relevant specifically to vaccines, we decided to systematically identify, summarise, and catalogue current frameworks and taxonomies on vaccines. We sought to then connect these dimensions to a general framework for communicating evidence to inform coverage decisions (i.e., the EtD framework). We explored differences among the existing frameworks specific to vaccines and compared these with the wider EtD framework in order to inform the EtD framework with specific and comprehensive dimensions and criteria related to the adoption or modification of immunisation policies. 2. Methods The research was structured in three phases. In the first phase, we developed a comprehensive literature search to identify conceptual frameworks on vaccines. In the second phase, we identified and synthesised the main dimensions and constructs suggested. In the third phase, we provided specific suggestions on target vaccine adoption decisions to inform the EtD framework. 2.1. Criteria for considering studies for inclusion We included systematic reviews, which summarised frameworks for vaccine adoption decision-making. We considered as a systematic review any review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant research, and to collect and analyse data from the studies that are included in the review [12]. We excluded studies presenting: (a) no frameworks for vaccine adoption decision-making; (b) providing a narrow focus on a single dimension (e.g., cost-effectiveness studies); (c) basic scientific research on vaccine development; and (d) data on non-human vaccinations. To ensure the comprehensiveness of our review, we also included primary studies (i.e., conceptual studies describing or proposing a set of decision criteria or a decision-making tool), which were not included in the selected reviews. To identify these primary studies providing a new approach not previously described in the included reviews, we crosschecked the reference lists of all included reviews against the output of the search strategies. All relevant studies were included, regardless of their language or publication status. 2.2. Search methods for identification of eligible studies We searched for systematic reviews published between January 1990 and March 2013 on the following bibliographic databases: MEDLINE, EMBASE, The Cochrane Library (i.e., Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database, and NHS Economic Evaluation Database). Our search strategy featured the following keywords: decision-making, vaccination, decision aid, model, framework, health policy, and immunisation programmes. In order to consider primary studies that were not included in reviews, we performed a sensitive search strategy on MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials between March 2010 and March 2013 (the final date of the searches reported in Burchett et al. [13], the most recent systematic review on our subject). In addition to bibliographic databases, we searched the following websites: WHO, National Institutes of Health, Centers for Disease Control and Prevention, European Centre for Disease Prevention and Control and Pan American Health Organisation. To identify papers that were not indexed in the above-mentioned

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Records identified through systematic reviews (SRs) databases searching (1990-2013) (n = 2920)

Records identified through primary study databases searching (2010 -2013) (n = 997)

Full-text articles excluded, with reasons: - No decisional frameworks (n = 53) - The framework (for primary studies) was included in a SR (n = 9) - A vaccine economic analyses (n = 10) - Not study design of interest (n = 13) - Focused on non-human vaccinations (n = 1)

Full-text articles assessed for eligibility SRs (n = 23) Primary studies (n = 75)

Studies included in qualitative synthesis (n = 14) - 5 SRs (2 found by hand searches) - 9 primary studies

Fig. 1. Flow diagram.

databases, we examined the reference lists of all included studies for additional literature. 2.3. Data collection and analysis 2.3.1. Study selection Two authors independently examined the titles and abstracts retrieved by the search strategy and assessed the full-text articles of the potential relevant studies. Any disagreement was resolved by discussion. We documented the reasons for excluding studies. A study flow diagram according to the PRISMA statement [14] can be found in Fig. 1. 2.3.2. Data extraction and management We extracted information on the purpose of the study, the publication date, the origin and targeted country, primary results and decisional frameworks and taxonomy used. All doubtful information were presented to a third author and discussed before inclusion. Given the heterogeneity of study designs, their descriptive nature and lack of a standard methodology, we did not assess the methodological quality of the included studies. 2.4. Development and analysis of the conceptual framework We first recorded all of the components about coverage recommendations proposed in the included studies, assessing the frequency of each. We were inclusive, as we did not exclude items based on their relevance or frequency. We then used the EtD model to structure the identified components [8,9], aligning the terminology used in the vaccine frameworks to corresponding ones of the EtD. In particular, we organised our vaccine framework to present the information by dimensions and criteria. In EtD, the broader headings involve the main domains to be assessed (i.e., burden of illness or problem, benefits and harms, values and preferences, resources use, equity, and feasibility). The criteria for each domain are then presented as subheadings (e.g., incidence, efficacy, cost-benefit, etc.) placed at

subsequently narrow levels of the proposed hierarchy. Again, we retained all components found across included studies, although we might have modified the relationship between the domains and the criteria as intended by the original study authors. This entire process was carried out by a multi-disciplinary group of 12 review authors, including methodologists, policy makers, economists, and medical editors. The authors participated in extensive face-to-face and electronic correspondence. A few authors met in person on several occasions to consider all comments and refine the conceptual framework. We regularly circulated the document among authors who approved the final decisional framework. 3. Results 3.1. Search results We identified 2920 reference citations after excluding the duplicates. Among them, 98 potentially relevant publications were retrieved in full text (Fig. 1). Eighty-six publications were excluded because they: lacked a decisional framework for community vaccine adoption (n = 53) or an appropriate study design (e.g., narrative reviews) (n = 13); provided a narrow focus on a single dimension (e.g., economic analysis of vaccines) (n = 10); focused on nonhuman vaccinations (n = 1), or addressed a framework already described in an included review(n = 9)(see additional file 1). We identified three additional systematic reviews [13,15,16] as well as nine primary studies [17–25] that were not included in the systematic reviews. We selected an additional two reviews through hand searches [26,27], leading to a total of 14 included publications. 3.2. Description of systematic reviews and primary studies included All systematic reviews included were published after the year 2000. All were in English and the locations of the primary authors were from Canada [26], United Kingdom [13], Italy [27], Austria

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[15], and Mexico [16]. Each review included a range of 5–85 primary studies. Two of the reviews focused on developing a theoretical framework to support rational vaccination decision-making based on the available scientific literature [15,27], while the reviews of Bryson et al. [26] and Burchett et al. [13] reviewed the literature on national decision-making regarding the adoption of new vaccines. The former included the characteristics of National Immunization Technical Advisory Groups (NITAGs), which provide expert advice to government decision-makers. The latter analysed the frameworks included using a grounded theory approach to search for themes and categories that emerged from the criteria included. The review by Tapia-Conyer et al. [16] assessed the evidence-basis of the Commission for the Future of Vaccines in Latin America (COFVAL) and feasibility in order to discuss each recommendation in the context of existing vaccine-preventable diseases control strategies. The nine primary studies were in English language. Of these, seven targeted different geographic and cultural contexts: two publications focused on a middle-income country (South Africa) [18,21], one on low to middle-income countries [24], two on the national immunisation policy of developed and high-income countries (United States, South Korea) [17,25], while two was applied to malaria-endemic countries [19,22]. The remaining two studies focused on accelerating the adoption of new vaccines in Global Alliance for Vaccines and Immunization (GAVI) eligible countries [23] as well as a proposal for embracing the GRADE approach in the development of immunisation related WHO recommendations [20]. We present a qualitative description of the five systematic reviews and the nine primary studies in additional files 2 and 3. 3.3. The conceptual framework For each publication, we extracted the dimensions and the criteria proposed as well as the use of a methodologically rigorous system to develop the framework (e.g., GRADE approach) (Table 1). We then removed redundant terms of similar concepts (e.g., “economical and financial issues” or “economic data”) across studies and identified 10 dimensions repeated across the frameworks: Importance of illness or problem, Vaccine characteristics (benefits and harms), Values and preferences, Resource use, Impact of vaccine, Acceptability, Feasibility, Equity and ethical considerations, Legal and political considerations, and Decision-making. We quantified the frequency of each dimension across the conceptual frameworks in the included studies (Table 2). The most common dimensions were: Importance of illness or problem, Vaccine characteristics, Resource use, Decision-making and Feasibility. We extracted the criteria reported in the frameworks, organised them into the 10 dimensions identified, and assessed the frequency of each (Table 3). The most common criteria report across frameworks was Health economic analyses. The criteria Vaccine efficacy and effectiveness and Vaccine safety, which were under the dimension Vaccine characteristics (benefits and harms), were reported in almost all frameworks. In the dimension Importance of illness or problem, the criteria Incidence, Prevalence, Mortality, Social impact and Specific risk groups were most frequently mentioned. Regarding the use of a methodologically rigorous system to inform the frameworks in included studies, Ahmed et al. [17], Duclos et al. [20], Piatti [27] and Tapia-Conyer et al. [16], proposed the use of GRADE approach [10] for the information about the vaccine effectiveness and safety. Piatti [27] and Blecher et al. [18] indicated how they obtained the data to inform each dimension of the framework. For example, Blecher et al. [18] noted that their dimension Burden of disease was informed by data reported by the National Department of Health; their dimension Effectiveness of the vaccine was informed by data from published studies in reputable

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international journals, if possible, meta-analysis or Cochrane reviews (see Table 1). Eight of the frameworks analysed in Table 1 [16–23,25–27] reported that they considered guidance and recommendations from WHO guidelines [5]. After carefully reviewing the frequency, hierarchy, and reciprocal relationship of the vaccine framework components reported across studies, and standardizing the terminologies to develop our 10 dimensions and criteria, we proceeded to link the 10 dimensions to those of the general EtD framework, grouping some dimensions together. In fact, we were able to consider dimensions specifically proposed for vaccines to relate to other interventions such as drugs. The concepts outlined in the EtD were comprehensive, allowing us to align constructs and criteria proposed in the vaccines frameworks with those of the EtD. Various dimensions such as Importance of illness or problem, vaccine characteristics and impact of the immunisation programme, and resource use were consistently repeated across vaccine frameworks, despite small differences in the exact terms used to describe each. For instance, variations to describe the dimension Importance of illness or problem included burden of illness, seriousness of the problem, and number of people affected; the terms vaccine benefits and harms and impact of vaccination or immunisation programmes were used interchangeably to signify vaccine characteristics. These terms were grouped under the umbrella of the EtD dimension named vaccine characteristics and impact of the immunisation programme. In other cases, the relationship between vaccine frameworks and the EtD framework was less straightforward. For instance, Acceptability, Legal and political considerations, and Decision-making were placed under the umbrella of Feasibility. Thus, our final framework may have altered the original constructs intended by authors in the original papers. Table 4 presents the six dimensions of the EtD adapted to the vaccine context. The dimensions are Burden of disease, Vaccine characteristics and impact of immunisation programme, Values and preferences, Resource use, Equity and Feasibility. Each dimension is followed by a brief description and its corresponding criteria. For example, the main criteria for the Burden of disease dimension includes Frequency of the disease/condition (e.g., incidence), Severity of the disease/condition (e.g., mortality), and Social impact of the condition (e.g., hospitalisation rate).

4. Discussion This review analysed existing frameworks on the adoption of new vaccines in order to develop a comprehensive strategy that includes the most relevant and critical components for decisionmakers. The dimensions proposed across vaccine frameworks aimed to inform and support coverage decisions (e.g., decisions by third party payers about whether and how much to pay for vaccines). The taxonomy of different frameworks featured a sufficient level of overlap. Overall, Burden of disease, Vaccine characteristics, Resource use, Decision-making, and Feasibility were frequently reported across frameworks as the key factors to be considered in vaccine adoption decision-making, while Values and preferences and Acceptability were less consistently reported. These dimensions largely overlapped with those recommended for the assessment of any technology by policy-makers [28]. We a priori thought that a framework on vaccines would differ from that of other interventions such as drugs. However, after creating the framework and comparing it with EtD, we found that there were large areas of overlap such that the EtD was helpful in structuring the dimensions of the vaccine framework. It is important that the dimensions address pragmatic factors and directly link to coverage decisions.

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Table 1 Conceptual frameworks and empirical approaches analysed. Studies

General description

Dimensions and criteria

Ahmed et al., 2011 [17]

The framework is based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [10].

- Balance of benefits and harms: review of the baseline risk for disease and the expected relative and absolute effects on vaccination on health outcomes. - Type of evidence: evidence is grouped into four categories, with the order reflecting the level of confidence in the estimated effect of vaccination on health outcomes. - Values and preferences: relative importance of outcomes related to benefits, harms and cost. - Health economic analyses: cost-benefit, cost-utility, cost-effectiveness.

Blecher et al., 2012 [18] Ngcobo and Cameron 2012 [21]

The framework considers guidance and recommendations from WHO [5]. The decision to introduce a new vaccine in South Africa is based on local data.

- Disease burden and public health priority: incidence, morbidity and mortality of the condition; the public health significance of the condition (Data reported by the National Department of health). - Efficacy and safety (Published studies in reputable international journal, if possible meta-analysis or Cochrane reviews). - Cost-effectiveness: local studies are usually required, given very different cost structures across countries. - Total cost and affordability: depends on fiscal space, prioritisation, success in price negotiations and contracting. - Feasibility of implementation and availability of a credible implementation plan (If there are doubts about feasibility, pilot studies may be useful). - International guidelines and advice of the South African National Advisory Group on Immunisation (NAGI) and other local and international experts. - Political process: besides the technical aspects, the budget process also involves communication between the Ministers of Health and Finance and approval by a wider committee of Ministers, the national Cabinet and Parliament.

Brooks and Ba Nguz, 2012 [19] Milstien et al., 2010 [22]

The framework considers guidance and recommendations from WHO [5] for introducing new vaccines for malaria.

- Malaria disease burden: reported and confirmed cases by age group; reported malaria-related deaths by age group; malaria epidemiology profile by district; malaria cases in pregnant women and HIV + population. - Other malaria interventions: impact of current malaria interventions; coverage of current malaria interventions; cost-effectiveness estimates of current malaria interventions. - Malaria vaccine impact: impact on mortality and morbidity by age group. - Economical and financial issues: cost-effectiveness estimates of malaria vaccine. - Malaria vaccine efficacy, quality and safety: adverse events; interaction with other vaccines; efficacy.

Bryson et al., 2010 [26]

Factors considered by countries when making recommendations by presence of NITAGs.

- Burden of disease - Economic evaluation - Feasibility of local vaccine production - Feasibility of recommendation - Recommendations of other countries - Public perception - Vaccine safety and vaccine effectiveness

Burchett et al., 2012 [13]

Nine broad categories of criteria which may influence decisions on vaccine adoption.

- Importance of the health problem: burden of disease data, political priority, costs of disease, perceptions of importance. - Vaccine characteristics: efficacy, effectiveness, safety, deliver issues. - Immunisation programme considerations: feasibility, supply. - Acceptability - Accessibility, equity and ethics. - Financial/economic issues: economic evaluation, incremental costs, funding sources, vaccine price, financial sustainability, affordability. - Impact: impact on health outcomes and on non-health outcome, effect of co-administration, risks of serotype replacement. - Alternative interventions: cost–effectiveness of alternatives, effectiveness of alternatives. - Decision-making process: Evidence sources/quality of evidence, actors involved, procedures, cues to action.

Cho, 2012 [25]

The framework considers guidance and recommendations from WHO for introducing new vaccines in Korea [5].

- Disease burden in Korea: clinical characteristics of the disease, incidence, mortality, and case fatality rates. - Analyzes data on the efficacy, effectiveness, and safety of the vaccine: Sources of information on the vaccine include clinical trials conducted both in Korea and in other countries, WHO position papers, recommendations published by the U.S Centers for Disease Control and Prevention and the European Centre for Disease Prevention and Control. - Economic data: the cost, affordability, and financial sustainability of implementing the new vaccine programme, as well as the vaccine’s cost-effectiveness. - Recommendations by sub-committees and the KCDC: isolation of the patients, the prophylactic management among the patient’s contacts, the diagnostic methods, the disease surveillance and the immunisation.

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Table 1 (Continued) Studies

General description

Dimensions and criteria

Duclos et al., 2012 [20]

The framework considers guidance and recommendations from WHO [5] adopting the GRADE approach [10].

- Epidemiologic features of the disease: disease burden (including age specific mortality, morbidity, and social impact), specifics risk groups, epidemic potential, disease occurrence over time (i.e., secular trends), serogroup or serotype distribution (for serogroup or serotype specific vaccines), changes in epidemiological features over time. - Clinical characteristics of the targeted disease: clinical management, disease severity and fatality, primary/secondary/tertiary care implications, long-term complications and medical care requirements. - Vaccine and immunisation characteristics: efficacy, effectiveness and population impact of the vaccine (including herd immunity), safety, indirect effects, cold chain and logistical concerns, vaccine availability, vaccine schedule, social and programmematic acceptability of the schedule, ability to reach the target populations, ability to monitor programme impact. - Economic considerations: cost of illness, vaccine and vaccine delivery costs, potential for vaccine price reductions, cost-effectiveness of immunisation programmes, affordability of immunisation. - Health system considerations: possible interactions with other interventions and control strategies, possible impact of vaccine adoption on the wider health system. - Social impacts - Legal considerations - Ethical considerations

Levine et al., 2010 [23]

This is proposed framework based on observations of the process and drivers of new vaccine adoption in Global Alliance for Vaccines and Immunisation (GAVI) eligible countries. Considers guidance and recommendations from WHO [5].

Establish and organise evidence: - Epidemiology and burden of the disease (including the distribution of serotypes or strains if relevant to vaccine policies). - Evidence based on the safety, efficacy and relative cost effectiveness of the vaccine as a solution. Establish supportive global policies: - Vaccine recommendations. - Financing policies - Procurement mechanism Translate polices into local action: - Political will to implement - System to deliver and monitor

Makinen et al., 2012 [24]

Principal factors considered in decision-making processes of new vaccine adoption in lower-middle-income countries (LMICs).

- Burden of disease data (e.g., mortality and morbidity) - Cost related drivers: vaccine market information, cost-effectiveness, budget impact and affordability, and available financing. - Other decision-making factors: the experience of neighbouring countries, access to adequate procurement mechanisms and the role played by global/regional bodies to engage countries. - Recommendations include making epidemiological data and vaccine market information accessible to countries, building and reinforcing related analysis capacity, and promoting more efficient procurement mechanisms such as pooling.

Piatti, 2011 [27]

The decision-making procedure is divided in five analytical steps. For each step are provided methods and indicators, one of them is the GRADE approach [10].

- Step (1) Safety: Adverse Events (nature and frequency); Risk factors and groups at risk; Biological effects (biological disequilibrium) of the vaccine. - Step (2) Medical-Socio-Sanitary Aspects: Burden of disease, including the social impact of the disease; efficacy, vaccine coverage. - Step (3) Cost-efficacy analysis: direct and indirect cost, modelling; discounting; vaccine effectiveness; alternative scenario evaluation. - Step (4) Other implementation-related aspects: legal aspects; ethical aspects and equity. - Step (5) Priority: Integration of the above-mentioned points with the sense of urgency for introducing it.

Piso and Wild, 2009 [15]

The decision-making procedure is divided in seven analytical steps. Elements belonging to the first step were considered more important and incisive in shaping the decisional process than the following ones.

- Step (1) Public health relevance and alternative measures, immunisation strategy, conformity of programmes, research questions. - Step (2) Disease considerations: burden of disease, clinical manifestations, current treatment, epidemiology, risk groups and risk factors, social impact and other preventives measures; Vaccine considerations: vaccine characteristics, supply, administration schedule, immune response, efficacy and utilisation, population effectiveness and safety. - Step (3) Cost-effectiveness analysis. - Step (4) Considerations on acceptability and feasibility of the new programme, equity and ethical implications, legal and political considerations, potential side effects. - Step (5) Final decision: decision-making process itself. - Step (6) Implementation. - Step (7) Surveillance of vaccine coverage and utilisation, of epidemiologic changes, the frequency and nature of adverse events, immune surveillance and re-evaluation (revision).

Tapia-Conyer et al. [16]

The evidence-basis of the Commission for the Future of Vaccines in Latin America (COFVAL) and feasibility.

- Burden of disease and vaccine coverage - Epidemiological surveillance - National health accounts - Regional vaccination reference schemes - Professionalising immunisation policies and practices - Vaccine Advisory Committees - Innovative financing mechanisms for purchasing vaccines

10 5 6 4 12 11

Many of the dimensions and criteria presented in the included systematic reviews and primary studies were broad, lacking practical details for effective application in the evaluation or comparison of vaccine strategies to guide vaccine adoption decision-making. The benefit and safety of vaccines, for example, were not sufficiently addressed. At the same time, most frameworks were generally qualitative: they did not report key issues such as the study designs to privilege, how to assess the risk of bias, how to analyse benefits and risks (e.g., which relative and absolute measures to use), the value to award patient reported outcome measures and the minimal important differences. In order to be effective in their implementation, dimensions and criteria should have supporting documents that present summaries of quantitative and qualitative information with graphical and tabular displays. Governmental immunisation technical advisory panels advise regional and national authorities on decisions to introduce new vaccines or to adjust existing immunisation strategies. These authorities are commissioned to perform their own analyses (e.g., effectiveness or economic) based on existing studies that are not fully generalisable to local contexts due to differences such as disease epidemiology, vaccine-specific issues (e.g., distribution and replacement of serotypes), magnitude of estimated herd immunity effects, local immunisation strategies, effective coverage, local health care systems, budgets and vaccination policies [29,30]. The panels are likely to face difficulty re-adapting or re-interpreting data pertaining to relevant vaccine dimensions and criteria, which may introduce several problems and lower the quality of their recommendations. Policy makers must often support recommendations on the introduction of new vaccines without a transparent, structured and independent assessment process. This frequently occurs in situations characterised by considerable external pressure from the general public and those with vested interests [31–33]. Expert opinions may vary greatly as the unstructured approach leads to selective reporting of dimensions that confirm a priori beliefs [34]. A structured approach is necessary to guide stakeholders through the process, prompting them to consider all available evidence, including less comfortable topics such as the harms of the intervention [35]. The DECIDE project aims to provide empirically-based information on how recommendations are formulated and performed to support coverage decisions [8]. This approach is building on the substantial experience and knowledge of the GRADE Working Group [10]. In our study, we compared the DECIDE approach to other frameworks, revising it to specifically target vaccine adoption decisions. There is limited empirical research on how to convey detailed information to policy makers on adopting and implementing new vaccinations. No studies have examined the impact of a decisional framework on vaccines for policy makers. However, the lack of any structured framework and mechanism to ensure equitable access to vaccines and other benefits from research on infectious diseases raised controversies and tensions over the past years [36–38]. The limited results produced by these negotiations have stimulated calls for a structured global framework to improve equitable access to vaccines [39]. 4.1. Limitations

Total

Ahmed et al., 2011 [17] Blecher et al., 2012 [18] Ngcobo and Cameron 2012 [21] Brooks and Ba Nguz, 2012 [19] Milstien et al., 2010 [22] Bryson et al., 2010 [26] Burchett et al., 2012 [13] Cho 2012 [25] Duclos et al., 2012 [20] Levine et al., 2010 [23] Makinen et al., 2012 [24] Piatti, 2011 [27] Piso and Wild, 2009 [15] Tapia-Conyer et al., 2013 [16]

1 X X X X X X X X X X X X X X X X X X

12

X

3

7

X X X X

X

X

X X X

X X X X X X X X

X

X X X X X X X X

X X X X

X X X X X X

X X X X X X X X X

X

Feasibility Acceptability Impact of vaccination Economic considerations/Resource use Values and preferences Vaccine characteristics (benefits and harms) Importance of illness or problem

Dimensions Studies

Table 2 Dimensions considered across conceptual frameworks and empirical approaches.

X X

X X

X

Equity and Ethical considerations

Legal and political considerations

X

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Decisionmaking

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The main limitation of our study is the absence of a critical appraisal of studies included in our framework. Thus, some of the conclusions of this review may come from studies that are susceptible to bias. We also analysed the frequencies of dimensions combining systematic reviews and primary studies. Dimensions proposed by systematic reviews might have greater value than those proposed in primary studies. Moreover, we focused only on vaccine frameworks. The age of the primary studies included in the

Table 3 Criteria considered across conceptual frameworks and empirical approaches. Dimension

Criteria

Studies mentioning criteria and frequency Ahmed et al., 2011 [17]

Blecher et al., 2012 [18] Ngcobo and Cameron 2012 [21]

Importance of illness or problem

Values and preferences

Vaccine characteristics Biological effects of the vaccine Vaccine efficacy and effectiveness Vaccine coverage Population impact of the vaccine Herd immunity Vaccine safety Interaction with other vaccines Indirect effects Cold chain and logistical concerns Vaccine administration schedule Social and programmatic acceptability of the schedule

Burchett et al. 2012 [13]

x

x x x x

x x x

x

x x

x

Cho 2012 [25]

x x

Duclos et al., 2012 [20]

x x

x

x x

x

x x

x

Makinen et al., 2012 [24]

x x x

x

Piatti 2011 [27]

x

x

x

x

x

TapiaConyer et al. 2013 [16]

Total

x x x

x

6 4 5 5

x

x

x x

x x

3 5 1 2 5 1

x

2

x

x

3

x x

x

2 2 2

x

1

x

x

Piso and Wild 2009 [15]

x

x x x

x

Levine et al., 2010 [23]

x

x

x

x x

x

2 3

x

x

x

11

x

1 1

x

x

x

x x

x

x

x

x x

x

x x

x

x x

x

x

x

x

1 11 1 1 2

x

x

3 1

1 1213

Relative importance of outcomes related to benefits

Bryson et al. 2010 [26]

M. González-Lorenzo et al. / Vaccine 33 (2015) 1206–1217

Vaccine characteristics (benefits and harms)

Burden of disease data Prevalence Incidence Mortality/Case fatality rates Morbidity Social Impact Hospitalisations Risk factors Specific risk groups Disease occurrence over time (i.e., epidemic, secular trends) Serogroups or serotypes distribution Clinical features of the disease Clinical management Cost of disease Perceptions of importance Other preventives measures

Brooks and Ba-Nguz 2012 [19] Milstien et al., 2010 [22]

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Table 3 (Continued) Dimension

Criteria

Studies mentioning criteria and frequency Ahmed et al., 2011 [17]

Blecher et al., 2012 [18] Ngcobo and Cameron 2012 [21]

Impact of vaccination

Bryson et al. 2010 [26]

Burchett et al. 2012 [13]

Cho 2012 [25]

Duclos et al., 2012 [20]

Levine et al., 2010 [23]

Makinen et al., 2012 [24]

Piatti 2011 [27]

Piso and Wild 2009 [15]

TapiaConyer et al. 2013 [16]

Total

Relative importance of outcomes related to harms Relative importance of outcomes related to cost

x

1

x

1

Health economic analyses (e.g., cost-benefit, cost-utility, cost-effectiveness) Direct and indirect cost Vaccine and vaccine delivery costs Potential for vaccine price reductions Affordability of immunisation Cost-effectiveness of alternatives interventions Incremental costs Funding sources Financial sustainability

x

x

Acceptability of the vaccine Public perception

Feasibility

Feasibility of the implementation of the programme Feasibility of local vaccine production and vaccine availability Feasibility of recommendation Ability to reach the target populations

x

x

x

x

x

x

x

x

x

x

x

x x

x

x

x x x x

1

x

3 x

3

x x

1 2 3

x

x

3

x

x

2

x

x

1

x

1

x

1 x

2 1

x x

x

12

x

x

x

x

1 5

x

x

x

Impact on health outcomes Impact on non-health outcomes Effect of co-administration Risk of serotype replacement Other impact

Acceptability

x

x

x

x x

x

4

x

3

x

2

x

2

M. González-Lorenzo et al. / Vaccine 33 (2015) 1206–1217

Economic considerations/Resource use

Brooks and Ba-Nguz 2012 [19] Milstien et al., 2010 [22]

Equity and Ethical considerations

Ethical considerations Accessibility, equity and ethics

Legal and political considerations

Legal considerations

Decisionmaking

Decision-making process Evidence sources/quality of evidences Impacts and coverage of other interventions for the disease Population coverage Priority Actors involved Procedures Cues to action Recommendations of other countries International guidelines and expert advice Political process

x

x

x

x

x x x

x

4

x

1

3 3

x x

x

x

x

x

x

5

x x

x

4 2

x

x

x

x x x x x x x

2

x

x x

x

x

3

x

1 1 1 1 1 1

M. González-Lorenzo et al. / Vaccine 33 (2015) 1206–1217

Impact of vaccine adoption on the wider health system. Ability to monitor programme impact (i.e., surveillance) Epidemiological changes of the disease (after vaccine introduction)

1 x

2

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Table 4 Proposed conceptual framework to support vaccine adoption and coverage decisions in a health system. Dimensions

Description

Questions

Criteria

Burden of disease

Description of epidemiology, clinical features and sequelae of the disease/condition in terms of public health consequences.

Is the disease/condition severe? Is the disease/condition frequent? Is the vaccination a priority?

Vaccine characteristics and impact of immunisation programme

Description of the effects and adverse events of the vaccine; using the GRADE method. Overall quality of the available evidence of effects across all of the outcomes, which are critical to making a decision.

Values and preferences

Consideration of values and preferences of patients/care givers about the balance between desirable and undesirable effects of the vaccine.

Resource use

All the information about costs, use of resources and health outcomes gained.

Equity

Impact on health inequities and ethical considerations.

Feasibility

Information on applicability and possible barriers, acceptability, organisational impact, alternative scenarios, control system.

Are the desirable anticipated effects large? Are the undesirable anticipated effects small? What is the net benefit of the vaccination? What is the overall certainty of this evidence (e.g., how confident we are about the net benefit of the vaccination)? How certain is the relative importance of the desirable and undesirable outcomes? Would patients/caregivers feel that the benefits outweigh the harms and burden? What is the appreciation and value of the vaccination in the population? Is the incremental cost small relative to the net benefits? Is the total cost (impact on budget) small? What are the costs of the vaccination and are they limited compared to the benefits? What would be the impact on health inequities? Would some part of the population taking advantage from the vaccination compared to other groups? Is the option feasible to adoption in the actual setting? Which vaccination barriers or facilitators act at the system level?

- Frequency of the disease/condition (e.g., incidence, prevalence, secular trends). - Severity of the disease/condition (e.g., mortality, morbidity). - Social impact of the disease/condition (e.g., hospitalisation rate, sickness absenteeism, high-risk groups, clinical features, perception of importance, other preventive measures) - Vaccine characteristics or properties (e.g., components, types, target population, posology). - Efficacy (e.g., immunogenicity, strain coverage, capacity to reduce the disease incidence, capacity to disrupt carriage, duration of protection, serotype replacements). - Safety (e.g., reactogenicity, adverse events, interaction with other vaccines)

systematic reviews of frameworks is limited. Most studies were developed only in the last 15 years. Most reviews incorporated overlapping contents with a narrow focus. However, decisionmakers may differ in the way they conceptualise their problems and approach decisions given the availability of support tools suitable for use in other clinical areas as well. If vaccines are not different from other interventions, particularly drugs, a systematic review with a broader perspective might have added other relevant elements. Our work serves as a starting point to define and develop a usable framework to inform vaccine coverage decisions. Future directions involve addressing the above conceptual and methodological issues and increasing their broader applicability. This process should include key stakeholders as well international groups leading the development of support tools for clinical decision-making such as the GRADE and the DECIDE Working Groups [8,10]. Another consideration is that decisional frameworks quickly evolve, shaped by the changes in professional and social contexts as well as secular trends. For example, the EtD framework we used as

- Values and preferences of citizens about the balance between desirable and - undesirable effects of the vaccine. - Perspectives and perceptions of the citizens and health professionals about the disease and the vaccine.

- Vaccination costs (e.g., costs of the vaccine, administration costs, costs arising from potential adverse effects). - Budget impact and financial sustainability. - Health economic analyses (e.g., cost-effectiveness analysis, cost-benefit analysis, cost-utility analysis) - Direct and indirect costs. - Ethical considerations - Equity (e.g., accessibility; equal distribution of resources, benefits risks, costs, etc. related to the vaccination programme).

- Acceptability of the vaccination among the population and health care professionals. - Feasibility of the implementation of the programme (e.g., vaccination coverage, ability to reach the population target, vaccine availability and supply, recommendation). - Alternative interventions (e.g., effectiveness and cost-effectiveness of alternatives). - Surveillance system.

a comparison tool was released as an interim version in December 2013 [8]; the finalised version has yet to be released and might differ from the interim version.

5. Conclusions The prospect for a framework to support coverage decisions on vaccines is promising as national interests favour equitable access to vaccines and drugs and reduce the threat posed by preventable diseases. Our study identified a number of frameworks with a variety of dimensions. Burden of illness or problem, vaccine characteristics, values and preferences, resource use, equity and feasibility are key factors. Our review highlights limitations in the dimensions and criteria as well their lack of detailed and pragmatic instructions for effective application in the evaluation or comparison of vaccine strategies. Moving forward, future studies should evaluate ways to effectively communicate and support the uptake of evidence pertaining to the selected dimensions and

M. González-Lorenzo et al. / Vaccine 33 (2015) 1206–1217

criteria, providing empirically-based and user-tested information about alternative ways to present criteria and their perceived utility in supporting policy decision-making. Conflict of interest The authors declare that they have no competing interests. Authors’ contributions MGL, AP, LC, MG, FA and LM conceived of the study. VP participated in the search strategy. MGL and LM participated in the design of the study, performed data extraction and coordination of the study. MGL, LM, AM, VD, EP, MT and AZ participated in the analysis. All authors read, provided feedback, and approved the final manuscript. Support The research leading to these results was primarily supported by a grant from the Regione Lombardia, Italy. Elena Parmelli received support from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n◦ 258583 (DECIDE project). Acknowledgements We thank Koren H. Kwag for their copyediting support, and Andy Oxman and Stefanos Bonovas for their comments on a previous draft of this essay. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.2014. 12.020. References [1] Manzoli L, Flacco ME, D’Addario M, Capasso L, De Vito C, Marzuillo C, et al. Nonpublication and delayed publication of randomized trials on vaccines: survey. Br Med J 2014;348:3058. [2] Walker CL, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, et al. Global burden of childhood pneumonia and diarrhoea. Lancet 2013;381(9875):1405–16. [3] Whitney CG, Zhou F, Singleton J, Schuchat A. Benefits from immunization during the vaccines for children program era—United States, 1994–2013. Morb Mortal Wkly Rep 2014;63(16):352–5. [4] Hutubessy R, Henao AM, Namgyal P, Moorthy V, Hombach J. Results from evaluations of models and cost-effectiveness tools to support introduction decisions for new vaccines need critical appraisal. Bio Med Cent Med 2011;9:55. [5] World Health Organisation. Vaccine introduction guidelines. Adding a vaccine to a national immunisation program: decision and implementation; 2010. [6] World Health Organisation. Principles and considerations for adding a vaccine to a national immunization programme. From decision to implementation and monitoring; 2014. [7] CDC global health global immunization strategic framework 2011–2015. http://www.cdc.gov/globalhealth/gid/framework/.. [8] Treweek S, Oxman AD, Alderson P, Bossuyt PM, Brandt L, Brozek J, et al. Developing and Evaluating Communication Strategies to Support Informed Decisions and Practice Based on Evidence (DECIDE): protocol and preliminary results. Implement Sci 2013;8:6. [9] Parmelli E, Amato L, Saitto C, Davoli M. DECIDE: developing and evaluating communication strategies to support informed decisions and practice based on evidence. Recenti Prog Med 2013;104(10):522–31. [10] Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Br Med J 2008;336(7650):924–6. [11] Work Package 2: Policymaker and manager focussed strategies for communicating evidence-based recommendations. http://www.decidecollaboration.eu/WP2..

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