Recommendations for rotavirus vaccination: A worldwide perspective

Vaccine 28 (2010) 5100–5108

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Recommendations for rotavirus vaccination: A worldwide perspective Carlos Rodrigo a,∗ , Nuran Salman b , Vladimir Tatochenko c , Zsofia Mészner d , Carlo Giaquinto e a

Department of Paediatrics, University Hospital Germans Trias i Pujol, Autonomous University of Barcelona, Barcelona, Spain Institute of Child Health, Istanbul, Turkey c Child Health Research Centre, Russian Academy of Medical Services, Moscow, Russia d National Institute of Child Health, Budapest, Hungary e Department of Paediatrics, University of Padova, Padova, Italy b

a r t i c l e

i n f o

Article history: Received 16 October 2009 Received in revised form 19 April 2010 Accepted 30 April 2010 Available online 14 May 2010 Keywords: Rotavirus Guidelines Vaccine

a b s t r a c t Official guidelines are crucial for new vaccines to be accepted by physicians and policy makers, and for reimbursement decisions, particularly for vaccines against diseases with an under-appreciated burden, such as rotavirus gastroenteritis (RVGE). Evidence-based guidelines, which take into account the best available data, ensure that new vaccine introductions achieve the greatest sustainable impact. For rotavirus vaccination, guidelines are specific to the locality for which they are developed, reflecting, for example, potential differences in disease burden, prevalence of co-infections (e.g. human immunodeficiency virus) and existing vaccination schedules. By adapting existing evidence-based guidelines, local strategies can be devised to optimise protection against RVGE in different settings. © 2010 Elsevier Ltd. All rights reserved.

1. Introduction In response to the global burden posed by rotavirus gastroenteritis (RVGE), two rotavirus vaccines (RotarixTM , GlaxoSmithKline Biologicals, Rixensart, Belgium and RotaTeqTM , Merck & Co. Inc., Whitehouse Station, NJ, USA) have been developed and made available worldwide. RotarixTM is an oral, human vaccine containing the human G1P [8] rotavirus strain, derived from the 89 to 12 parent candidate [1]. RotaTeqTM is an oral, bovine–human reassortant vaccine that contains five live reassortant strains of rotavirus (G1P [5], G2P [5], G3P [5], G4P [5] and G6P [8]), derived from bovine (Wistar calf 3 [WC3]) and human strains [2]. Both vaccines can be administered to infants from the age of 6 weeks, and protection against RVGE has shown to extend over the first 2 years of life [3–5], when the peak incidence of disease occurs [6]. High efficacy against severe RVGE has been successfully demonstrated in Phase III trials in Europe [4,5], the United States (US) [5], Latin American countries [3] and Asia [7], with preliminary data emerging from Southern Africa [8]. Large clinical studies show the vaccines to be well tolerated when co-administered with other childhood immunisations, with no evidence to suggest any long-term safety concerns [5,9]. Further data to support these conclusions are being collected through surveillance programmes, which monitor the safety profile of vaccines in practice [2,10–12].

∗ Corresponding author. Tel.: +34 497 8928; fax: +34 497 8843. E-mail address: [email protected] (C. Rodrigo). 0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.04.108

On the basis of the efficacy data available, widespread vaccination of infants is the intervention most likely to reduce the global burden of RVGE [13,14]. However, the nature of these benefits will depend on the socio-economic status of the country in question. Most deaths from RVGE occur in the world’s poorest nations, such as southern Asia and sub-Saharan Africa; these deaths are estimated to amount to more than 600,000 per year [15]. Limited access to medical provisions, such as oral rehydration solutions and hospital care is thought to contribute to the disproportionate mortality observed in some developing territories [15]. On the other hand, in Europe and other industrialised regions, the greatest burden from RVGE relates to the large number of medical visits and hospitalisations from the disease, as well as a high number of nosocomial infections [16–18]. In the absence of vaccination, RVGE has been estimated to cause 87,000 hospitalisations per year among children younger than 5 years in Europe [17] and 55,000–70,000 annual hospitalisations in the same age group in the US [19]. Wild-type antibodies to rotavirus have been detected in about one-third of infants by 6 months of age, two-thirds of infants by 1 year of age, and almost all infants by 2 years of age [20]. Using modelling techniques, it has been predicted that mass vaccination of infants would significantly reduce the health burden of RVGE in terms of the number of deaths, hospitalisations, emergency department visits and general practitioner visits [21–25]. Since RotarixTM and RotaTeq® were made available in 2006, guidelines and recommendations have been issued regarding their use [2,19,26–44]. These guidelines differ in their methodology, approach and target audience. Some are regulatory, outlining the legal use of the vaccine (e.g. dose, administration, contraindi-

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cations, etc.) [45–48], while others are designed from a public health perspective [19,27,29,30,32,33,36,38,39,42,44]. The latter are developed by policy decision makers, describing the official use of the vaccine within national immunisation calendars (e.g. universal mass vaccination, risk-group strategy, no vaccination, etc.). Guidelines can also take a scientific approach aimed at individual physicians, advising on the most appropriate use of the vaccine in a specific set of clinical circumstances [2,26,28,31,34,35,37,40,41,43]. The purpose of this review is to examine the need for, and associated public health benefits of, scientific guidelines for rotavirus vaccination, from a worldwide perspective. The methodologies used to develop guidelines are addressed, with a particular focus on the potential benefits of an evidence-based approach. Finally, we assess the practical application of existing guidelines at a local level, identifying aspects that are sensitive to local disease epidemiology and healthcare practices, and which could benefit from adaptation before implementation in developing or newly industrialised countries. 2. Search methodology MEDLINE abstracts between 2004 and 2008 were searched on 5 August 2008 using the search terms ‘rotavirus’ and ‘vaccine’. These dates were selected to identify only those guidelines and recommendations relating to the current rotavirus vaccines, RotarixTM and RotaTeqTM . Using these search terms a list of 643 references was generated. The abstract for each reference was reviewed to identify those of potential relevance to this article (N = 42). Any additional sources were identified from reputable websites, the bibliographies of these references or from the authors’ own libraries and expertise.

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weighed by the expected health benefits; (3) it must demonstrate vaccine safety on the population level (i.e. widespread vaccination should not have a major adverse effect on the population in the short or long term); (4) it must demonstrate cost-effectiveness (i.e., the intervention should be sufficiently cost-effective from the societal perspective) [52]. This process can result in official recommendations produced for policy decision-makers and that are potentially highly influential. This type of recommendation has a large impact on national vaccination implementation and funding. For example, in Belgium, official recommendations have led to copayment of rotavirus vaccines, and in Finland vaccines are provided free of charge. 3.2. Scientific guidelines and recommendations Scientific societies often generate clinical practice guidelines or recommendations alongside the development of official recommendations (e.g. European Society for Paediatric Infectious Diseases [ESPID], European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN], American Academy of Pediatrics [AAP]) [2,40]. The main purpose of these guidelines is to support healthcare professionals in making decisions regarding the most appropriate care in a specific set of clinical circumstances [53,54]. The methodology used for their development varies considerably, ranging from systematic, evidence-based medicine [55] to less well-defined procedures. 4. The needs and benefits of guidelines/recommendations 4.1. To provide information and guidance on the need to vaccinate

3. Process for developing guidelines/recommendations Countries that have formulated recommendations for rotavirus vaccination (official or by a scientific society) are shown in Table 1 [2,19,26–44,49,50]. 3.1. Official recommendations Regulatory documents are produced by official bodies (e.g. the US Food and Drug Administration [FDA] and the European Medicines Agency [EMEA]), which outline the official use of vaccines. These ‘summary of product characteristics’ or ‘product information’ documents do not provide guidance on who should or should not receive the vaccine in the context of national immunisation programmes. In developing countries, particularly those with less established regulatory systems, approval by the FDA or EMEA is often used to register vaccines in lieu of a local vaccine evaluation [51]. Variations in healthcare practices or disease epidemiology mean that guidelines are specific to the country or continent for which they were generated. Once a vaccine is licensed, it is evaluated for inclusion in national immunisation programmes, usually by groups of nationally appointed experts within health authorities (i.e., national immunisation committees such as the US Advisory Committee on Immunization Practices [ACIP]). The vaccine profile and available clinical data on safety and efficacy are considered, and placed in the context of the national healthcare system, disease epidemiology, any implementation issues, ethical and legal constraints and cost-effectiveness. For example, in Finland, a new vaccine must meet four predefined criteria: (1) it must have a public health benefit (i.e. there must be a considerable disease burden, and vaccination should be expected to alleviate this burden); (2) it must demonstrate vaccine safety on an individual level (i.e. the risks of vaccination to an individual should be minimal and be out-

Guidelines and recommendations can provide information and guidance on the need to vaccinate. From a public health perspective, guidance dictates whether a vaccine should be included in the national immunisation programme or offered only to risk groups. Alternatively, from an individual healthcare professional’s perspective (scientific society recommendations), guidance is offered on whether the vaccine should be recommended to their patients. For some diseases, the decision as to whether to vaccinate is straightforward, based on well-defined disease burden criteria and/or high mortality rates (e.g. for polio or smallpox). However, for other diseases with low mortality rates, such as RVGE, the decision is less clear-cut. Despite high awareness of diarrhoea, the causative agent is rarely diagnosed through laboratory testing, resulting in low general awareness of rotavirus and RVGE [56,57]. This can lead to the epidemiology and disease burden of RVGE being poorly defined, making prevention strategies more difficult to rationalise. However, evidence supporting the large contribution of rotavirus to diarrhoeal disease is growing. For example, estimates suggest that rotavirus is the most frequent cause of infantile gastroenteritis worldwide, accounting for about one-third of severe cases of RVGE requiring hospitalisation [58]. The decision-making process of whether a vaccine should be recommended considers local disease burden and cost-effectiveness (usually for public health recommendations only), whereas information on vaccine safety and efficacy can be extrapolated from studies conducted in other countries. 4.2. To promote acceptance of new vaccines within the medical community In a survey supported by European vaccine manufacturers, carried out in five European countries (France, Germany, Italy, Spain and the United Kingdom [UK]), 81% of the 5000 respondents from

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Table 1 Countries with recommendations for rotavirus vaccination and associated guidelines, by region. Continent

Country

Issuing body (year)

Type of recommendation (regulatory, official, scientific)

Recommend UMV

Published guidelines

Reference

Asia

Pan-Asian Bahrain

Pediatric Society of Thailand Ministry of Health (2008)

Scientific society Official

Yes Yes

Yes No

India

Indian Academy of Pediatrics Committee on Immunization (2008) Ministry of Health (2008)

Scientific society

Yes

Yes

Santosham et al., 2007 [26] Kingdom of Bahrain Ministry of Health, 2009 [27] Singhal et al., 2008 [28]

Official

Yes (from 2008)

No

WHO, 2008 [50]

ESPID/ESPGHAN (2008) Bundesministerium für Gesundheit (2009) Conseil Supérieur de la Santé/Hoge Gezondheidsraad (2006) Ministry of Social Affairs and Health (2009) The French-Speaking Group of Paediatric Gastroenterology, Hepatology and Nutrition (2007) La Ministre de la Santé (2006)

Scientific society Official

Yes Yes

Yes Yes

Official

Yes

Yes

Official

No

Scientific society

Yes (from 2009) Yes

Vesikari et al., 2008 [2] Bundesministerium für Gesundheit, 2009 [29] Conseil Supérieur de la Santé/Hoge Gezondheidsraad, 2007 [30] WHO, 2008 [50]

Yes

Olives, et al., 2007 [31]

Official

No

Yes

La Ministre de la Santé, 2006 [32]

Deutsche Akademie fur Kinderheilkunde und Jugendmedizin (DAKJ) (2006) Mitteilung der Standigen Impfkommission (STIKO) am Robert Koch-lnstitut

Official

No

Yes

Niethammer et al., 2006 [33]

Scientific society

Yes

Yes

Mitteilung der Standigen Impfkommission (STIKO) am Robert Koch-lnstitut, 2007 [34]

Italy Luxemburg

Italian Paediatricians (2008) Conseil Superieur d’Hygiène

Scientific society Official

Yes Yes

Yes Yes

Spain

Spanish Association of Pediatrics (2008) National Advisory Committee on Immunization (NACI) (2008) Advisory Committee on Immunization Practices (ACIP) (2006, 2009) American Academy of Pediatrics (AAP) (2007) Brazilian Society of Pediatrics (2006) Ministry of Health (2006)

Scientific society

Yes

Yes

Guarino, et al., 2008 [35] Conseil Superieur d’Hygiène, 2006 [36] Bernaola Iturbe et al., 2008 [37]

Official

Yes

Yes

NACI, 2008 [38]

Official

Yes

Yes

Parashar et al., 2006 [19]; Cortese et al., 2009 [39]

Scientific society

Yes

Yes

AAP, 2007 [40]

Scientific society

Yes

No

Feijo et al., 2006 [41]

Official

Yes

No

Brazilian Ministry of Health, 2006 [42] Munoz et al., 2006 [43]

Qatar Africa Europe

No guidelines identified Pan-European Austria Belgium

Finland France

Germany

North America

Canada

USA

USA South America

Brazil

Chile

Chilean Infectious Diseases Society (2006) Ministry of Health

Scientific society

Yes

Yes

Official

No

No

Ecuador

Ministry of Health (2007)

Official

Yes

No

El Salvador Honduras

Ministry of Health (2006) Ministry of Health (2008)

Official Official

No No

Mexico

Comisión Federal para la Protección contra RiesgosSanitarios (COFEPRIS; 2004) Ministry of Health (2006) Ministry of Health (2006) Ministry of Health (2006)

Official

Yes Yes (from July 2008) Yes

Official Official Official

Yes Yes Yes

No No No

Australian Government National Immunisation Program (2007)

Official

Yes

Yes

Australian Government, 2007 [44]

Official

Yes

No

WHO, 2008 [50]

Nicaragua Panama Venezuela Oceania

Australia

Micronesia

WHO, 2008 [50]; de Oliveria et al., 2008 [49]

No

ESPID, European Society for Paediatric Infectious Diseases; ESPGHAN, European Society for Pediatric Gastroenterology and Nutrition; EU, European union; n/a, not applicable.

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the general public considered healthcare professionals to be the primary source of information regarding vaccination of their children [59]. The attitude of healthcare professionals towards a particular vaccine is a major determinant to vaccine acceptance and uptake [60,61]. This strong link between the perception of healthcare professionals and vaccine uptake has been well documented in studies from around Europe and the US [59], and underlines the critical requirement for guidelines on new vaccines to be targeted not only to decision makers but also to paediatricians directly. The availability of recommendations for routine administration has been identified as pivotal for the adoption of a vaccination policy, organisation of funding, infrastructure, and the large-scale implementation of vaccination by clinicians on a national scale [57,62–64]. A survey of immunisation providers, belonging to either the Wisconsin or Georgia Chapters of the American Academy of Pediatrics, was conducted in the US in 2001 [62]. The purpose of this survey was to assess opinions on the reintroduction of rotavirus vaccines following the withdrawal of RotaShieldTM (Wyeth-Lederle Vaccines, New York, NY) in 1999 subsequent to concerns over an association with intussusception (a potentially life-threatening intestinal blockage) [62,65]. Of the 319 eligible responders, 93% confirmed that they would use a new, safe rotavirus vaccine provided that it was recommended by the AAP and ACIP [62]. In a separate survey conducted in 2004 (N = 747), 50% of eligible physicians indicated that they would stock and use a rotavirus vaccine that was recommended by the ACIP and AAP even if they did not perceive the vaccine as a major necessity [57]. Both surveys used ‘theoretical’ data for a new rotavirus vaccine, since they were conducted before the US licensure of RotaTeqTM in 2006 and RotarixTM in 2008. Two further surveys using ‘real data’ were conducted following the licensure of RotaTeqTM in the US [63,64]. One survey of sentinel physicians (N = 305) belonging to the AAP was conducted during January and February 2006 (i.e. before publication of the ACIP recommendations in August 2006 [19]). The report found a higher percentage of respondents were prepared to strongly recommend rotavirus vaccination to their patients if the ACIP made a recommendation for routine vaccination than if it made a recommendation for permissive vaccination (50% vs 33%, respectively) [63]. Furthermore, a slightly higher percentage of physicians would recommend rotavirus vaccination (strongly or otherwise) to their patients if the ACIP issued a recommendation for routine rather than permissive use of rotavirus vaccines (84% vs 76%, respectively) [63]. A second, interview-based survey was conducted among 10 board-certified or board-eligible paediatricians, or family medicine physicians who regularly administered immunisations in California or Missouri in 2006. These responses revealed that all physicians would recommend rotavirus vaccination to parents if the vaccine was recommended for use by the ACIP or AAP [64]. The results from these two surveys are supported by the increasing uptake of rotavirus vaccination in the US, as monitored by the Immunisation Information Systems (IIS) across 27 US states. This increase is likely to be related to the availability of the ACIP and AAP recommendations for routine infant administration of rotavirus vaccine. 4.3. To provide advice on reimbursement within national immunisation programmes Reimbursement of a vaccine within a national immunisation programme is the most effective way to ensure maximum uptake of vaccination. It is becoming increasingly necessary to evaluate the cost-effectiveness of vaccination, particularly in countries where a recommendation to include a vaccine in the national immunisation programme is directly linked to vaccine reimbursement [66]. Evaluation of cost-effectiveness is also especially relevant for the implementation of vaccination programmes against diseases with low mortality [67], such as RVGE in the industrialised world.

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Cost-effectiveness calculations are country specific and reflect local disease epidemiology, vaccine efficacy and the healthcare system. Some countries, such as the US, might consider indirect social costs of the disease (e.g. cost of lost working days and family disruption due to illness), together with direct healthcare costs (e.g. medical expenditure for hospitalisations, medical consultations and treatment) [39], while other countries, such as the UK, require a vaccine to be cost-effective from the perspective of the healthcare system [68]. The cost-effectiveness of rotavirus vaccination has been assessed in a number of countries. A study in the US concluded that while routine infant rotavirus vaccination may not be cost-saving from the healthcare or societal perspective (i.e. it cannot deliver health benefits and save money), it can still be considered costeffective (i.e. deliver health benefits at an acceptable cost) [24]. In Australia, rotavirus vaccination was found to be cost-effective and cost-saving from the societal perspective [22]. Similar findings were reported in eight Latin American and Caribbean countries and in The Netherlands [23,25]. Rotavirus vaccination was not found to be cost-effective in studies carried out in France and in England and Wales [21,69]. Clearly, the true value of a vaccine cannot be assessed from crude cost-effectiveness calculations that do not include accurate disease burden data (including nosocomial infections), and the cost of treating a sick child at home (time missed from work to care for children, the increased demand for nappies, wipes, etc.). Furthermore, quality-of-life parameters, from either the child’s or the family’s perspective, are rarely measured, despite being adversely affected by RVGE. In short, crude cost-effectiveness estimates such as those used in England and Wales do not take into account the full impact of the disease on families and wider society. It is the authors’ view that government advisory committees should ideally include experts in health economics. Such individuals should be able to influence the assumptions and structure of models used to evaluate the cost-effectiveness of vaccination, in order to capture the true impact of the intervention, and/or advise on the limitations of existing models. 4.4. To provide guidance on how the vaccines should be used safely and effectively and to prevent off-label use Guidelines are necessary to provide clear advice to healthcare professionals on the most appropriate use of a vaccine and to provide context to the issues surrounding regulatory product labelling. A study was carried out to assess the adherence of healthcare providers to the FDA-recommended age limits for vaccination with RotaTeqTM during its first 6 months of use (August 2006–January 2007) in Philadelphia, US. Overall, 770/3912 (19.7%) of first doses were administered to infants older than the maximum recommended age of 12 weeks [70]. The authors remark that one factor contributing to this substantial off-label use could be that awareness of the guidelines from the ACIP and AAP was not high, or that the guidelines were not available until some months later [70]. Minimising off-label use is particularly important for rotavirus vaccines, given the history of the first rotavirus vaccine, RotaShieldTM . The risk of intussusception in infants who received RotaShieldTM was approximately 20-fold that of age-matched controls within 3–14 days following the first dose, and 5-fold within 3–14 days following the second dose [65]. Eighty percent of intussusception cases occurred in infants who were 90 days or older at the time of the first dose, indicating that the risk was age dependent [71]. No vaccine-associated intussusception cases occurred among infants who received the first dose of RotaShield TM when they were younger than 60 days [71]. In light of these findings, recommendations for rotavirus vaccines adhere to the conditions used in large, phase III safety trials, as these studies showed no increased risk of intussusception following vaccination [5,9].

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A review of two data systems in the US (the six IIS sentinel sites and the Vaccine Safety Datalink [VSD]) between February 2006 and May 2007 indicated that the majority (95.0% and 98.6%, respectively) of infants vaccinated with the full three doses of rotavirus vaccine (RotaTeqTM ) received the first dose according to the thencurrent guidelines from the ACIP (i.e. between 6 and 12 weeks of age) [19,72]. A small percentage of doses were reported as being administered completely outside the recommended age range of 6–32 weeks (<0.2% doses administered below 6 weeks and <1.8% doses administered above 32 weeks) [72]. 4.5. Promote consistency in the use of vaccines National immunisation schedules vary with regard to local vaccination recommendations, even in regions with a similar disease epidemiology and burden, such as Europe [73]. These differences in national recommendations could be for several reasons, such as differences in local healthcare practices and methods of funding. It could also be due to varying interpretations of the same evidence, which is influenced by the level of local expertise of vaccinology [52]. The diversity in immunisation programmes could also suggest that they are not based on evidence, as the aim of each immunisation schedule should be to administer the minimum number of doses capable of guaranteeing effective protection [73]. Evidence-based guidelines can promote consistency in vaccination practices. In Europe, this could be beneficial with respect to the free movement of families with young infants: harmonisation would avoid the problems encountered when beginning an immunisation schedule in one country and completing it in another [73]. 4.6. To reduce the time investment per physician to research into the clinical data and potential benefits of new vaccines Many guideline documents summarise the rationale for vaccination and the best available clinical evidence into a concise and high-quality publication [2,19,40]. They are, therefore, valuable resources for busy healthcare professionals to gain a thorough understanding of a new health intervention, while minimising the time invested per individual physician. 5. Methods used for vaccine guideline development Given the importance of guidelines for practicing healthcare professionals and public health officials, it is essential that they are of high quality, taking into account the best available evidence. For medical interventions in general, evidence-based guidelines, developed through formal, systematic procedures, are receiving growing attention due to their transparency and explicit methodology (e.g. Delphi procedures, Grading of Recommendation Assessment, Development, and Evaluation [GRADE] methods [74], etc.) [54]. However, developing such guidelines is time consuming and requires specific expertise, therefore, a strict evidence-based approach has rarely been used, especially for vaccines [75]. Some of the established rotavirus vaccine guideline groups are reliant on expert working parties (e.g. the World Health Organization [WHO]), national consensus conferences (e.g. ACIP) or systematic literature reviews, whereas other guideline groups are not explicit about the methodology used to develop their recommendations. Recently, there has been a clear shift from expert-led group and experiencebased local guidelines towards national evidence-based guidelines to ensure that new vaccine introductions achieve the greatest sustainable impact [54,76]. Because strong evidence supporting an intervention is usually based on few large randomised controlled studies conducted worldwide, the development of national evidence-based guidelines requires the ‘contextualisation’ of international data and their inte-

gration with national information (e.g. cost-effectiveness models), without replicating the process for the evidence evaluation of large multinational studies. A framework for vaccine introduction decision-making for national immunisation programmes has been proposed by Andrus et al. [76]. This includes technical criteria (i.e. disease burden, vaccine characteristics, adverse events and post-marketing surveillance, cost-effectiveness and other economic evaluations), programmatic and operational criteria (i.e. vaccine supply, logistical and operational issues, financing strategies, and financial partnerships), and social criteria (i.e. perception of risk, political will and equity) [76]. Recognising that some developing countries may not have the resources available to make evidence-based decisions, particularly with regard to cost-effectiveness and economic evaluations of interventions, the ProVac initiative was launched by the Pan-American Health Organization (PAHO) in 2006 [76]. This initiative provides technical co-operation and strengthens national capacities to make evidence-based decisions by means of focusing on three essential factors: (1) decisions should be nationally rather than regionally based (to ensure the infrastructure is available to support vaccine introduction); (2) evidence used to support decisions must be broad based (including cost-effectiveness, financial stability and healthcare system infrastructure); and (3) the infrastructure must be in place to support a national process. As part of this work, a modelling tool has been developed to help countries use local data on disease burden and costs to conduct economic analysis of rotavirus vaccine introduction [77]. For scientific guidelines, the ESPID/ESPGHAN evidence-based recommendations for rotavirus vaccination in Europe represent the first evidence-based attempt of their kind [75]. In the absence of an official body empowered to issue recommendations on vaccination to European Union member states, it has traditionally been the role of individual countries to determine their own position on vaccine-related issues. The ESPID/ESPGHAN recommendations have challenged this perception, demonstrating the value of providing high-quality, evidence-based, consistent information to physicians across Europe. The strength of the ESPID/ESPGHAN recommendations lies in their evidence-based methodology, as described by Dr Mrukowicz [55]. In accordance with the formal protocol of the GRADE working group [74], the supporting clinical evidence for both available rotavirus vaccines (RotarixTM and RotaTeqTM ) was compiled into evidence tables, stating the methodological quality of the evidence, as well as the relative and absolute measures of efficacy (benefits) and adverse events (harms) with 95% confidence intervals. The evidence tables supporting the final recommendations of the ESPID/ESPGHAN are presented in the final publication to ensure transparency [55]. Given the amount of work invested in developing the evidence tables, they may also provide a tool for policy makers to base future national decisions on rotavirus vaccination in European countries. As part of the evidence-based process, each final recommendation is given a grade to indicate to the end user the confidence level of the guideline issuers that adherence to the recommendation would do more good than harm. This approach is being increasingly adopted and has been used by ESPID/ESPGHAN [2], the consensus statement from Italian Paediatricians [35], the ACIP [19] and AAP [40]. 6. Practical issues surrounding the development of rotavirus vaccination guidelines The move towards evidence-based guidelines will help avoid inappropriate decisions that are not supported by a sufficient body of high-quality evidence. Guidelines that are developed in this manner are suitable for adaptation (or adoption) by other countries, either within the continent for which they were developed, such as

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the ESPID/ESPGHAN evidence-based recommendations for Europe, or by other countries. In the latter situation, certain aspects of the recommendations are sensitive to country-specific epidemiology, healthcare system organisation, local values and preferences and should be considered carefully to ensure relevance to the new population. Adaptation of guidelines is also important as the risk criteria in developing or mid-developed countries are different from those in industrialised countries [51]. In reality, guidelines (e.g. ACIP) are often adopted by newly industrialised countries (e.g. Thailand or Brazil) without adaptation. This may happen because of a lack of accurate rotavirus disease burden information or a lack of expertise in adapting guidelines at country level [78]. The following section highlights areas of recommendations that could be considered sensitive and thus may require special consideration when adapting guidelines for developing or mid-developed countries. 6.1. Co-administration with oral poliovirus vaccine Since concomitant administration of two oral attenuated vaccines may interfere with the immune response to one or both vaccines, guidelines for rotavirus vaccination have taken different approaches when recommending whether current rotavirus vaccines should or should not be co-administered with oral poliovirus vaccine (OPV) [2]. In a large-scale clinical safety study in Latin America, RotarixTM was given 2 weeks apart from OPV [9]. However, administration of OPV during the 42-day period preceding the planned dose was a criterion for exclusion in the large clinical efficacy trials of RotaTeqTM . This inconsistency between vaccines may reflect differences in clinical trial locations–RotaTeqTM studies were carried out predominantly in US and European locations, where OPV is rarely used [5,79,80]. Preliminary data suggesting co-administration of the two vaccines did not interfere with the immune response to OPV (for all three strains), were available for RotarixTM in 2004 [81,82] and RotaTeqTM in 2007 [83]. Co-administration of rotavirus vaccine and OPV did not significantly interfere with the immune response to RotarixTM after a full course (two doses) given at 10 and 14 weeks of age [81,82], and to RotaTeqTM after a full course (three doses) given at 8, 16 and 24 weeks of age [83]. Due to the lack of data at the time at which the recommendations were produced, the ESPID/ESPGHAN took a conservative approach, not recommending co-administration of OPV and rotavirus vaccines in European populations (albeit with a weak-strength recommendation) [2]. However, unlike in European populations, use of OPV is common-place in many countries in the developing and newly developed world, creating the need for specific guidance on this matter. The 2006 recommendation from the Consultative Committee of Immunizations on behalf of the Chilean Infectious Diseases Society stated that RotarixTM (the only vaccine being used in Chile at that time) could be co-administered with OPV based on the preliminary data available [43]. Similarly, in other Latin American countries, rotavirus vaccines are administered simultaneously with other vaccines in the routine immunisation schedule, including OPV. For both licensed rotavirus vaccines, the final immunogenicity and reactogenicity results for co-administration with OPV were published in 2008 [84,85]. As these data suggest that coadministration with OPV has no impact on immunogenicity, they may be incorporated into new guidelines and updates of existing recommendations. 6.2. Vaccine efficacy The efficacy of oral vaccines in general may vary from one region of the world to another, potentially being lower in less affluent countries due to high levels of malnutrition and underlying diseases (e.g. human immunodeficiency virus [HIV] infection)

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which affect the immune response to vaccination [86–90]. Reasons for reduced rotavirus vaccine efficacy may more likely be related to interference from maternal antibodies in breast milk and/or maternal transplacental antibodies, or as a result of helmith infections affecting intestinal mucosal pathology [91]. Since differences in vaccine efficacy can affect the expected impact of vaccination and, in turn, the calculations of cost-effectiveness, it is important to consider local or regionally comparable vaccine efficacy data when developing guidelines. This sentiment was echoed by the WHO, who initially recommended rotavirus vaccination, but only for those countries with local vaccine efficacy data available [92]. In recognition of this fact, vaccine manufactures have taken a truly global approach in vaccine development, with local efficacy data being generated in different continents. For RotarixTM , Phase III studies have been conducted in particularly challenging environments such as Southern Africa. Preliminary results in South African infants are highly encouraging, showing vaccine efficacy of 82.7% (95% CI: 61.9–92.9) against severe RVGE and 66.5% (95% CI: 52.6–76.5) against any episode of RVGE [93]. The latest combined data from Malawi and South Africa indicate vaccine efficacy against severe RVGE of 61.2% (95% CI: 44.0–73.2). Although vaccine efficacy was lower in these countries, compared with Europe and Latin America, for example, due to more challenging setting, the impact of vaccination is likely to be substantial: an estimated 4.2 and 6.7 episodes of severe RVGE would be expected to be prevented per 100 children vaccinated in South Africa and Malawi, respectively, compared with approximately 1 in Latin America [8,9]. 6.2.1. Vaccination of HIV-infected infants Recommendations for the rotavirus vaccination of HIV-infected infants vary across different guidelines, reflecting the lack of data available. The EMEA do not recommend rotavirus vaccines for HIVinfected infants [45], and the ACIP state that data are insufficient from clinical trials to support administration to infants with indeterminate HIV status who are born to mothers with HIV [19]. Following the experience with other attenuated vaccines in HIVinfected children, the ESPID/ESPGHAN recommend vaccination of HIV-infected infants at the discretion of the physician, recognising that the benefits of vaccinating this population against RVGE could be high [2]. As the incidence of HIV infection is higher in developing countries, particular consideration should be given to the risk–benefits of vaccinating this population when adapting guidelines from countries or continents where HIV infection is less common. Initial results from a Phase II, double-blind, randomised, placebo-controlled study, designed to assess the safety, reactogenicity and immunogenicity of the human vaccine, RotarixTM , are encouraging. When co-administered with routine childhood vaccines to HIV-infected infants in South Africa (N = 100), the vaccine was immunogenic. The seroconversion rate was 57.1% (95% CI: 34.0%; 78.2%), similar to that observed in comparable populations of infants without HIV. Further, no concerns were raised regarding the reactogenicity and safety of the vaccine, and antibody response against all concomitant vaccines was similar in the placebo and vaccine groups, indicating that RotarixTM did not impair the immune response to other vaccines [94]. Preliminary findings from Southern Africa, where the incidence of HIV is relatively high, demonstrate RotarixTM as having a high efficacy against severe RVGE in this population, with no safety concerns [93,95]. Studies of RotaTeqTM in HIV-infected infants are ongoing [2]. 6.3. Vaccination of premature infants Limited evidence suggests that premature infants (younger than 37 weeks’ gestation) may be at increased risk of hos-

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pitalisation from viral gastroenteritis during their first year of life [96]. Although recommendations for administration of the vaccine to premature infants differ in their wording, it is generally accepted that vaccination of premature infants should be implemented at calendar age according to recommendations for healthy infants [2,19,28,35,38,40]. Guidelines from the ACIP and AAP state that practitioners should consider the potential risks and benefits for vaccinating this population. However, vaccination is supported in the following circumstances: if the infant is at least 6 weeks of age, is being or has been discharged from hospital, and is clinically stable [19,40]. Studies with RotaTeqTM indicate that the vaccine can be safely given to otherwise healthy infants older than 32 weeks’ gestation (median, 34 weeks’ gestation)[97] and that the vaccine is effective in reducing hospitalisation and emergency room admission after 2 years of follow up. Similarly, initial results from a study of the two-dose human vaccine RotarixTM in premature infants are encouraging. A Phase IIIb, double-blind, randomised, placebocontrolled, multi-country, multicentre study was designed to assess the safety, reactogenicity and immunogenicity of RotarixTM in infants born within a gestational period of 27–36 weeks. There was no statistically significant difference in terms of serious AEs between the vaccine and placebo groups. In addition, two vaccine doses were found to be immunogenic, with an antirotavirus IgA antibody seroconversion rate of 75.9% (95%CI: 56.5–89.7) in early pre-term (gestational age 27–30 weeks) and 88.1% (95%CI: 80.9–93.4) in late pre-term (gestational age 31–36 weeks) infants [98]. 7. Conclusions Rotavirus is responsible for a substantial disease burden in infants, parents and for healthcare providers worldwide. Although mortality is higher in developing nations, morbidity from RVGE is considerable in both industrialised and developing countries. Rotavirus vaccination is of benefit to all healthy infants, provides a high degree of protection against severe RVGE, and is the optimum choice for prevention of the disease. Availability of official guidelines/recommendations is crucial for any new vaccine to be accepted by physicians and policy makers and for reimbursement decisions, especially for diseases with an under-appreciated disease burden, such as RVGE. Recommendations from scientific societies are a valuable supplementary tool to promote best practice within the medical community. They also provide an important resource in the generation of official recommendations, and can ‘bridge the gap’ in situations where such guidelines have yet to be created. Guidelines for rotavirus vaccination are specific for the country or region for which they were developed. This reflects the relationship between disease burden and socio-economic status (i.e. mortality in developing countries, and morbidity in industrialised countries), as well as differences in local healthcare practices. Some of the world’s most highly populated regions recommend the universal rotavirus vaccination of healthy infants. Public health authorities or scientific societies now have the opportunity to adapt existing recommendations according to their local epidemiology, disease burden, vaccine efficacy and healthcare practices in order to continue to provide relevant guidance on how rotavirus vaccines can be used for maximum effect against the morbidity and mortality caused by RVGE. Conflict of interest Professor Mészner and Professor Nuran Salman declare no other conflicts of interest.

Acknowledgements The authors are grateful to members of the Paediatric ROTavirus European CommiTtee (PROTECT) for their feedback on the content on this manuscript. We would like to thank Alison Lovibond who provided medical writing assistance on behalf of Fishawack Communications Ltd. Development of the manuscript was supported by GlaxoSmithKline Biologicals. The PROTECT group and development of this manuscript were supported by a grant from GlaxoSmithKline Biologicals. Professor Carlos Rodrigo has received consultancy fees and independent research grants from GSK Biologicals, GSK, Sanofi-Pasteur MSD, Wheth, Pfizer, Astra-Zeneca and Astellas. Professor Vladimir Tatochenko has received honoraria from vaccine manufacturers for lectures and participation on expert advisory panels. Dr Carlo Giaquinto has received consultancy fees and independent research grant from GSK-Biologicals, GSK, SP-MSD, Merck, ABBOTT, BMS, Gilead, Boeheringer Ingelheim and Tibotec.

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