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Europe paper

The role of in reducing resistance (AMR) Executive Summary

The frequency of (AMR) is increasing in Europe and constitutes a serious danger to public . Without policies and actions to prevent the spread of AMR, the current 25,000 annual deaths in Europe could grow to 390,000 per year by 2050 and could lead to an era in which common and minor injuries are no longer treatable. Evidence has shown that existing vaccines have a positive impact in reducing AMR. In addition, new vaccines could play a critical role in preventing multi- resistant infections, such as from S. aureus, C. difficile and E. coli. To accelerate new research and development, private-public partnerships and multi stakeholder collaborations are needed for fundamental research and public authorities’ engagement, to improve and AMR surveillance. Recommended strategies for the reduction of AMR include the judicious use of and greater control measures, but EU and national AMR stewardship must include more comprehensive strategies in parallel that include effective prevention measures such as vaccination. Vaccination can play multiple roles in AMR reduction strategies, including: reducing the use of by preventing bacterial infections, e.g., conjugate pneumococcal vaccines; reducing the misuse of antibiotics by preventing viral for which antibiotics are inappropriately prescribed, e.g. vaccines; and preventing antimicrobial resistant infections from spreading; e.g. pertussis & Hib vaccines. These strategies must strive a wider use of these existing vaccines to maximize their impact on AMR through a life-long approach of the National Immunisation programmes and by integrating vaccination planning into EU and national action plans to be developed for the fight against AMR. Vaccines Europe’s members are already engaged in the development of vaccines against AMR pathogens and Healthcare Associated Infections (HAI). However, there is a need to engage all relevant stakeholders to more clearly define the priorities for the development of new vaccines against AMR pathogens and to establish the necessary tools to support this development. This support ranges from setting up robust and real-time disease and AMR surveillance and database to ensure that vaccine developers select appropriate pathogens, as well as to enhancing funding for early research in and immunology of AMR pathogens and HAI.

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Introduction Antimicrobial resistance (AMR) is the Definition of Antimicrobial resistance (AMR): reduction or elimination of the effectiveness The ability of a to resist the of antimicrobial agents to cure or prevent action of an antimicrobial agent. infectious diseases1. It occurs through Ref: ECDC1 in , or acquisition of genetic material from other , which increasingly prevalent in Europe, reaching neutralise or escape the effect of the 12.0% for third generation and antimicrobials. 22.4% for fluoroquinolones3. In the UK, between 1999 and 2011, E. coli - New antimicrobial resistance mechanisms resistant strains increased 7-fold9. have been evolving rapidly. Bacteria producing extended-spectrum β-lactamases Antibiotic resistance correlates with the use of (ESBLs), enzymes that allow bacteria to resist outpatient antibiotics10, 11, 12. several antimicrobials, first emerged in the 1980s but are now global in distribution2. Antimicrobial resistance makes it more They pose a major threat by limiting difficult to treat infectious diseases treatment options. The major cause of AMR in humans is the ecological pressure on microorganisms due to The frequency of antimicrobial the widespread use of antimicrobials. AMR resistance is increasing in Europe can arise from the misuse of antimicrobials in In most countries across the European Union, agriculture and in medicine. In veterinary use, antimicrobial resistance is occurring with several classes of antibiotics may be used in a increasing frequency but large inter-European rearing cycle, contributing to AMR for variations occur 1,3,4,5,6. There are both north- diseases that also affect humans. In medicine, to-south and west-to-east gradient for AMR, auto-, or inappropriate use of with generally lower resistance percentages in antibiotics in viral infections (often because of the north and higher percentages in the south the absence of a confirmatory or immediate and east3. These can most likely be explained diagnosis) contribute to the growing problem by different national practices and utilisation of AMR1. AMR makes some serious bacterial of healthcare. infections harder and more costly to treat and can lead to severe disease and deaths. The important vaccine-preventable AMR bacterium is no Antimicrobial resistance constitutes a longer susceptible to both and serious danger to in 0 – 37.8% of isolates from 28 In May of 2014, the World Health Assembly European countries, and resistance rates are requested (in resolution WHA67.2513) that a >5% in 14 of these countries3. global action plan on antimicrobial resistance Other AMR pathogens include carbapenem- be developed. This in light of a global resistant for which consensus that antimicrobial resistance poses resistance rates had risen in some European a profound threat to human health14. countries to up to 33% by 20147. Likewise, The European Commission15, the European methicillin-resistant strains of Staphylococcus Council16, and the European Centre for aureus (MRSA) infections account for more Disease Prevention and Control (ECDC)1, all than 10% of S. aureus infections in 15 agree that antimicrobial resistance constitutes European countries, and several countries a serious danger to public health in Europe, have resistance rates closer to 50%8. the ECDC reporting that the continuous Antibiotic-resistant strains are

Page 2 of 14 spread of carbapenemase-producing through direct protection of vaccinated Enterobacteriaceae (CPE), ( including E. coli, K. individuals, and by reducing the carriage (the pneumoniae and Enterobacter species, etc.), colonisation of an individual in the absence of “presents a serious threat to healthcare and disease), whereby limiting the spread of patient safety in European hospitals”3. infections within a community (herd ). It is estimated that 25,000 deaths from AMR occurred in EU countries in 201117. Without The reduction in the number of infections policies and actions to halt the spread of from vaccination is a result of both direct and AMR, the 25,000 deaths in Europe could grow herd protection. In the US, for instance, after to 390,000 every year by 205018, and cost $ the introduction of 13-valent conjugate 2.9 trillion in OECD countries17 (as much as $ (PCV 13) in children, 100 trillion globally by 2050 in lost global AMR invasive pneumococcal disease declined productivity19). The WHO warns that AMR in both the vaccinated and some could lead to a post-antibiotic era in which unvaccinated age groups ()20. A common infections and minor injuries are no similar phenomenon was noted after the longer treatable2. earlier introduction of PCV 7, and the implementation of PCV1021, 22, when herd Limiting the misuse of antimicrobials immunity decreased acute otitis media- and preventing infections can related health care utilization in unvaccinated contribute to a reduction in young children23. antimicrobial resistance Reducing bacterial infections: Vaccination can Recommended strategies for the reduction of reduce the of AMR by reducing AMR include the judicious use of the total number of cases of infectious antimicrobials and infection control measures. disease (though direct and indirect protection But these strategies alone are not sufficient. - herd effect), by reducing the number of More comprehensive approaches to circulating AMR strains, and by reducing the combatting AMR, such as through the use of need for antimicrobial use. AMR was other available and under-utilised tools, like becoming a problem before Haemophilus vaccination, are needed. Longer-term influenzae type b (Hib), S. pneumoniae, and strategies include research and development Neisseria meningitidis vaccines were of better diagnostics, novel antimicrobials and introduced, but these vaccines have reduced vaccines against additional infectious or nearly eliminated circulation of AMR for 14, 19 diseases . strains covered by the vaccines24. Following Vaccination plays multiple roles in widespread use of pneumococcal vaccines, the of AMR related invasive strategies aimed at preventing the pneumococcal diseases was largely reduced in direct health consequences of AMR all ages in the US and Europe25, 26, 27, 28, 29. Hib infections as well as reducing vaccine has virtually eliminated the ampicillin- antimicrobial resistance resistant infection caused by H. influenzae 24 Vaccination can prevent the direct health type b . consequences of serious vaccine-preventable Reducing viral infections: Viral infections infectious diseases, prevent deaths and often lead to secondary infections (bacterial complications, and reduce healthcare costs, infections that occur on top of viral including costly hospitalisations. infections). In persons with laboratory Vaccination can reduce AMR by reducing the confirmed influenza, reported rates of number of infectious cases in the population, bacterial secondary infection range from 2%

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(in newborns) to 65% (in adults)30. The most immediate diagnosis)34. A review from common bacterial secondary infections in Western Europe found that antibiotics influenza were found to be S. pneumoniae were prescribed to children with and S. aureus, 35% and 28% of infections, influenza in 28% to 55% of cases34. respectively30. The inappropriate prescription of antibiotics increases the exposure of Reducing the number of viral infections, bacteria to widely used antimicrobial through vaccination, can in turn reduce the agents, and leads to the development total number of cases of bacterial secondary of antimicrobial resistance. infections, and therefore reduce the use of antimicrobials. Conjugate pneumococcal For influenza, the most appropriate vaccination, in turn, can reduce the incidence strategy for reducing the of viral respiratory infections31. inappropriate use of antibiotics is vaccination. Several studies have Both viral and bacterial vaccines have the demonstrated that antibiotic use for potential to reduce community reliance on influenza related illnesses may decline antimicrobials. Influenza vaccination has been by as much as 64% after influenza demonstrated to reduce use of antibiotics by vaccination is introduced1,33, 36 . as much as 64% in vaccinated individuals, by reducing the incidence of disease, thereby 3. Prevent antimicrobial resistant reducing the number of associated infections from spreading. antimicrobial prescriptions (for secondary With approximately 35 million elderly bacterial infections or for misdiagnosed admitted to hospital per year in the influenza)32Error! Reference source not found.. The role of US and EU (a group especially at-risk vaccination in strategies to reduce of antimicrobial-resistant infections), antimicrobial resistance is threefold19: vaccines could significantly reduce the 1. Reduce the use of antibiotics by current risks of AMR spread in preventing bacterial infections (S. institutional settings19. pneumoniae, H. influenzae type b, In adults, hospitalisation rates for Neisseria meningitides, Bordetella pertussis substantially increase with pertussis, Mycobacterium age, so wider implementation of dTap tuberculosis, etc.) and prevent viral boosters in adults and older adults infections (such as influenza and could reduce hospitalisation rates and varicella) for which bacterial limit exposure to AMR pathogens in secondary infections are common the hospital37. (every year S. aureus causes an estimated 150,000 bacterial infections In infants and young children, secondary to varicella33). vaccination substantially reduces hospitalisation and the rate 2. Reduce the misuse of antibiotics, by of hospital acquired infections and so preventing viral diseases for which can likewise limit the risks of exposure antibiotics are inappropriately to AMR pathogens in hospitals38. prescribed.

Antimicrobials are often inappropriately prescribed for influenza or other upper respiratory tract viral infections (usually in the absence of a confirmatory or

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Public health and scientific bodies have alternative treatment and prevention options 42 recommended vaccination be included including vaccines” . Scientific bodies have endorsed or echoed these in strategies aimed at reducing recommendations43. The Council has called on antimicrobial resistance Member States to have national action plans Because vaccination directly or indirectly against Antimicrobial Resistance in place reduces the use of antibiotics, limiting the before mid-2017, and on the EU Commission opportunity for antimicrobial resistance to to develop a new and comprehensive EU arise, scientific bodies and public health Action Plan on Antimicrobial Resistance, authorities consider vaccination a key based on the One Health approach. intervention in the fight against antimicrobial resistance. In view of the ongoing development of national and EU policies to combat AMR, this The WHO recognizes the importance of paper highlights some of the major challenges vaccination as one of the most cost- and needed policies for better implementation effective public health interventions, and the of vaccination programs and vaccine research, important role of vaccination in reducing in support of the fight against antimicrobial 39 AMR . And the Review on Antimicrobial resistance. Resistance recently concluded that “a much more robust pipeline of new vaccines” is Vaccines can help to address needed to help contain growing AMR40. the current challenges posed by Vaccination strategies recommended to combat AMR include14, 19: AMR if vaccination programs in

1. wider use of vaccination in humans EU Member States are and animals to maximise coverage strengthened with available vaccines; Childhood vaccination programs have been 2. more vaccine research, especially for enormously successful, having a huge impact diseases where scientific barriers on human health over the last 50 years, from exist; and, the control of both viral and bacterial 3. creating the conditions for a viable diseases40, and often saving society more than 17 and sustainable vaccine market . 10 times their cost44. However, vaccine- preventable diseases also have a significant The EU Commission and Member impact on adult mortality, health and quality of life. Adult vaccination has been given less States are called to develop sound emphasis than other health priorities and its antimicrobial resistance policies and an benefits to society are not well recognised. action plan by mid-2017 With the EU population ageing, and the In 2009, the EU Council conclusions on incidence of non-communicable diseases innovative incentives for effective antibiotics rising (increasing the risk of serious recognised that “a wide range of measures is complications from infectious diseases), needed to ensure that currently available better preventive measures against infectious antibiotics remain effective for as long as diseases are urgently needed. Groups such as possible, such as effective vaccines to prevent the ESCMID Vaccine Study Group (EVASG), the infections”41. In June 2016, the EU Council on European Geriatric Medicine Society the next steps under a One Health approach (EUGMS), the World Association for Infectious to combat antimicrobial resistance, called on Diseases and Immunological Disorders Member States to “encourage the use of (WAidid)45, and the European Federation of

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Internal Medicine46, now recommend a life- Vaccination coverage in infants in some long approach to vaccination, where the countries is decreasing52, and emphasis on vaccines for children is extended outbreaks continue to occur where to include better health through vaccination vaccination coverage in children is not of working-age adults and the elderly. optimal, either because of non-completion of vaccination boosters, or because of delayed Very few countries in the EU have a or refused vaccination53. comprehensive strategy for adult vaccination and few have good vaccination coverage data and , virtually eliminated in for working age adults and the elderly, with childhood, now occur predominantly in adults the exception of influenza47. in Europe, due to low vaccination coverage with booster vaccines51, 54. The reasons are multiple: To better contribute to AMR reduction  lack of recommendations for some strategies, comprehensive life-long newer vaccines; vaccination programs are needed, and  lack of reimbursement for countries should take practical actions recommended vaccines; towards their implementation, in particular  limited information of vaccination for for working age adults and the elderly. working age adults and the elderly and some high-risk groups; Importance of improving vaccination in  lack of knowledge and complacency healthcare workers amongst healthcare workers and the Several bacterial infectious diseases (like public; pertussis or the secondary bacterial infections  . of viral diseases) are more easily transmitted Far more infections could be prevented in and/or acquired in healthcare settings. Europe by establishing programmes with a Healthcare associated infections (infections life-long approach to vaccination and acquired by patients receiving healthcare) are appropriate implementation of these among the leading causes of preventable programmes. For influenza alone, it is deaths and are associated with a substantial estimated that, each year, Member States fall increase in health care costs each year. short of the coverage target of 75% by almost Because of the extensive use of 60 million persons, resulting in around 2 antimicrobials, the healthcare environment million additional cases of influenza48. Only acts as a breeding ground for Clostridium two member states reached the 75% difficile, and antimicrobial-resistant bacteria influenza vaccination coverage target in the like Pseudomonas aeruginosa and E. coli. The 2012–13 influenza season. A majority of later carries a very high risk of mortality, at 19 countries had less than 50% coverage, and approximately 10 % . Mortality from almost half of the countries had lower Carbapenem-resistant Enterobacteriaceae coverage than in the previous influenza (CRE) infections, which mostly occur in 7 season1. Reducing influenza cases can reduce healthcare settings , may be as high as 75%, 55 the use of antimicrobials by up to 64%33, 36, 50. likely because of limited treatment options .

In spite of the observed herd immunity and Due to their contacts with multiple patients, reduction of antimicrobial use from healthcare workers play a major role in cross- pneumococcal conjugate vaccination20, 21, patient disease . For influenza, childhood and elderly pneumococcal vaccination of healthcare workers is critical vaccination coverages are sub-optimal in for preventing the spread of the disease. several EU Member States47, 51. Preventing disease, in turn, can curtail the use

Page 6 of 14 of antibiotics and limit the opportunities for New vaccines for C. difficile, P. aeruginosa, S. antimicrobial-resistant bacteria to arise. The aureus59, and extra-intestinal E. coli are World Health Organisation recommends projected to become available in the next 3 to vaccination for healthcare workers against 6 years. several diseases56. R&D for vaccines is long, complex, and Vaccines in development against nosocomial carries high risks infections could prove very useful for high-risk Vaccine development is lengthy (between 8 groups, for instance those scheduled for and 18.5 years, on average). The risks are elective surgeries, or at risk of urinary tract, considerable: for every 5000 – 10,000 drug skin, and respiratory infections. and vaccine candidates that enter early research, about 250 will make it to preclinical The challenges of new vaccine testing, only about 5 will make it into clinical development to address AMR testing, and only one will make it to market60. pathogens The technical and regulatory requirements are While existing vaccines reduce the use of complex and contribute to the increased antibiotics for the infections that they investment needs and risks in this type of 61 prevent, new vaccines could play a critical role industry . in preventing multi-drug resistant infections, For example, the requirements for extensive such as from S. aureus and extra-intestinal post-marketing pharmacovigilance on newly 55, 57 pathogenic E. coli . licensed vaccines increase manufacturers’ 60 While the EU has not ranked the AMR requirements for resources . pathogens of greatest concern, for example Vaccine R&D is limited by the state of the US has done so to prioritise its research efforts58: scientific knowledge For many of the AMR pathogens, scientific  E. coli: resistance to 3rd generation challenges inhibit vaccine development19. cephalosporins and to These challenges include the lack of fluoroquinolones; immunological correlates of protection for  K. pneumoniae: resistance to 3rd some diseases, or the absence of good animal generation cephalosporins and to models for research. Additionally, insufficient carbapenems; bacterial genotype and serotype surveillance  S. aureus: methicillin resistance, or may limit knowledge for vaccine MRSA; development. And progress in basic  S. pneumoniae: resistance (non- immunology, such as for the development of susceptibility) to ; reference assays, with special attention to the  Non-Typhoidal Salmonella (NTS): immune responses of the elderly, is needed to resistance to fluoroquinolones ; advance vaccine R&D.  Shigella species: resistance to Vaccine R&D is challenging for diseases fluoroquinolones ;  Neisseria gonorrhoeae: reduced that occur in specific risk groups or susceptibility to 3rd generation environments cephalosporins. Vaccine development is especially challenging in some specific populations, such as the Other pathogens, such as multidrug resistant hospitalised elderly, and tuberculosis and Group B Streptococcus, are immunocompromised, where poor immune 58 included in the list of national concerns . responses, poorly documented epidemiology

Page 7 of 14 and a requirement for a large number of Table 1. List of vaccines in the pipeline against subjects may all challenge successful vaccine pathogens for which AMR is a serious development. And recruitment into clinical concern64, 65. trials may additionally be challenged by issues surrounding informed consent, the role of Vaccine Clinical stage of Total caregivers, and high morbidity and mortality development number in

62 in this population . pipeline Public-private partnerships (PPPs) are critical for future vaccine R&D Phase I Phase II Phase III These PPPs should cover: Clostridium difficile 2 1 3 Fundamental research for understanding immunology and pathogenesis Funding for research in fundamental Carbapenem- resistant immunology and related sciences, are critical 2 2 for identifying appropriate target Escherichia coli and new technologies for developing novel vaccine design concepts. Extra-intestinal Escherichia coli Strong and reliable disease surveillance 1 1 where good database and networks are key Moraxella Robust disease and AMR surveillance, and the catarrhalis + creation of national and supranational Non-typable 1 1 healthcare databases, are necessary to ensure Haemophilus that appropriate pathogens are selected for influenzae Mycobacterium vaccine development. Projects that aim to tuberculosis evaluate disease burden, such as the 1 4 5 Innovative Medicines Initiative (IMI) project on C. difficile infection (a partnership between Pseudomonas the European Union and the European aeruginosa ) are highly 1 1 valuable63. Staphylococcus aureus 2 2

Group B Streptococcus 1 1

Streptococcus pneumoniae 1 1

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Engage in continuous dialogue Wider use of existing vaccines to with all relevant stakeholders to maximize their impact on AMR  Encourage EU Member States to improve accelerate vaccine development vaccination coverage in all age groups, for new vaccines that address through a life-long approach, in order to reduce the use and misuse of antibiotics, AMR and integrate vaccination planning into A recently published paper by the UK national plans for the fight against AMR. independent Review on Antimicrobial Resistance highlights that many vaccines that Implement additional measures to are not on the market or even in early stages facilitate new vaccine development of development could play a crucial role in against AMR pathogens 40 tackling . The report  Set up robust disease and AMR concludes that there is a need for a much surveillance and database to ensure that more robust pipeline of new vaccines to help vaccine developers select appropriate contain rising drug resistance. pathogens and monitor their evolution. Early and continuous dialogue throughout  Enhance funding for early research in development could be established with all epidemiology and immunology of AMR relevant stakeholders (regulators, HTA / pathogens and HAI, for instance, to define NITAGs’ bodies, payers) to optimise mechanism of immunity and correlates of development plans and speed up the protection against AMR bacteria, evaluation of regulatory files so that these particularly in the elderly population. vaccines could reach patients earlier.  Engage in continuous dialogue with all relevant stakeholders (regulators, HTA Call for action to maximise the bodies, and payers) to accelerate vaccine development for AMR pathogens and HAI. impact of vaccination on AMR To be successful, AMR reduction strategies must include vaccines as a complementary approach, and to maximise the benefits they must strive to:

VE November 2016

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