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16 Eurohealth Observer

QUANTIFYING THE BENEFITS OF IN COMBATING RESISTANCE

By: Mark Jit, Michael Anderson and Ben Cooper

Summary: is one of the most effective measures to reduce . As vaccines are highly specific to their targeted pathogens, they are less likely to induce resistance compared to . Their impact on resistance or prescriptions has already been demonstrated for vaccines against pathogens such as Streptococcus pneumonia and , but greater investment and development is needed for vaccines which target pathogens such as Vibrio cholerae, Salmonella typhi, Escherichia coli, common health care-associated and respiratory and diarrhoeal . To value vaccines correctly, economic evaluations need to take account of multiple health system, ecological and epidemiological pathways through which vaccination affects antimicrobial resistance and use.

Keywords: Vaccines, Economic Evaluation, Antimicrobial Resistance

Introduction strains. This is because vaccines work by enabling the to recognise The development and use of vaccines is that are highly specific to their a key strategy to combat antimicrobial targeted pathogens. In contrast, antibiotics resistance (AMR). A recently published can impose selective pressure on both Mark Jit is Professor, chapter ‘The role of vaccines in combating targeted and non-targeted microorganisms , Department of antimicrobial resistance’ within the book; Infectious Epidemiology, to develop resistance. Second, due to the Challenges in Tackling Antimicrobial London School of Hygiene & specific nature of vaccines, vaccines can Tropical Medicine, and Principal Resistance: Economics and Policy be developed that target specific strains Mathematical Modeller, Statistics, Responses offers a comprehensive review Modelling and Economics Unit, of a pathogen that are most pathogenic of this summary. 1 In this article we National Infections Service, Public or prone to developing resistance. This provide an overview of the key issues Health England, London, UK; has been the case with pneumococcal Michael Anderson is Research discussed in the chapter. Officer, Department of Health conjugate vaccines, where the serotypes Policy, London School of Economics selected for vaccine development were Vaccines have a number of characteristics and Political Science, London, UK; generally the ones most likely to cause Ben Cooper is Associate Professor, which make them particularly effective invasive disease. 2 Thirdly, vaccines and Nuffield Department of Medicine, at combating AMR. First, vaccines University of Oxford, Oxford, UK. can work in a synergistic usually have little effect on the evolution Email: [email protected] fashion – vaccines can reduce the rate of microorganisms besides the targeted

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at which populations are infected and not targeted by the vaccine, such as the resistant strain, leading to declines hence extend the time until a pathogen commensal bacterial pathogens, as a in resistance in both hospitals and evolves resistance to an antimicrobial. result of reduced antibiotic selection the community. Finally, vaccines can be administered pressure. For example, since influenza only a few times and provide long-lasting infections are frequently treated with Priorities for vaccine investment and population-wide effects by preventing antibiotics (either inappropriately for the development to tackle AMR the onset of disease. In contrast, primary viral , or for a secondary antimicrobials need to be continuously bacterial infection), an effective and Vaccines are already used effectively to administered with each infection. While widely used vaccine that reduces the tackle AMR in many countries. In the they can be used prophylactically to number of influenza infections should , the introduction of the prevent disease onset, more commonly result in population-wide reductions in seven-valent pneumococcal conjugate they are used to treat rather than prevent antibiotic use. vaccine (PCV7) was associated with infections. They also have less potential to an 84% reduction in multidrug-resistant prevent onward of resistant Pathway 3: Infection severity effects invasive pneumococcal disease. 5 In microorganisms, as there is usually a delay the Canadian province of Ontario, the Vaccines that reduce the risk of between the onset of infectiousness and introduction of a universal influenza symptomatic infection without reducing receiving treatment. immunisation programme was associated the risk of carriage/asymptomatic with reductions in prescriptions of infection can lead to reductions in the antimicrobials for respiratory tract proportion of infections which are treated infections. 6 However, to fully capitalise with antimicrobials and therefore a on the benefits of vaccines to tackle The reduction in the selection pressure for AMR there are a number of vaccine resistant phenotypes. potential benefit investment and development needs which need to be prioritised. of vaccines to Pathway 4: Subtype selection effects Some vaccines may target subtypes of Vibrio cholerae a pathogen population which are more reduce AMR is Resistant and multi-resistant is likely to be resistant. As a result, overall a significant issue for many health care resistance may decrease. However, it is frequently systems. An oral which is also possible that vaccines may target effective at preventing medically-attended subtypes which are less likely to be underestimated cholera already exists. 7 Use of this resistant. In these circumstances, overall vaccine clearly has the potential to reduce resistance may increase. Pathways by which vaccines can AMR through its direct effect on cholera; reduce AMR‘‘ however, there is a need for greater Pathway 5: Interspecific effects investment to increase access to this The potential benefit of vaccines to Bacteria and viruses interact in vaccine, particularly in low and middle reduce AMR is frequently underestimated complex ways. For example, influenza income countries (LMICs). because people only consider a subset or respiratory syncytial (RSV) of the pathways by which vaccines can infections may increase the risk of Salmonella typhi affect antimicrobial use and resistance. secondary bacterial infections and In total, we consider six pathways by A ciprofloxacin-resistant lineage of patients with certain viral infections which vaccines can reduce the burden of Salmonella typhi infection has emerged may transmit more bacterial pathogens. AMR. 3 4 in many countries. Two vaccines have Vaccination against one organism could been available since the 1990s and are therefore reduce transmission of another, Pathway 1: Preventing infections by focal recommended by the World Health leading to declines in both resistant and pathogens Organization (WHO): the live Ty21a sensitive phenotypes. vaccine and the Vi-polysaccharide Vaccines may reduce the vaccine. 8 While they are both effective, of infection by a resistant pathogen. Pathway 6: Selective targeting effects their protection is partial and relatively This can occur both through direct Interventions, such as hygiene short-lived, typically up to two years. protection to those vaccinated, and improvements or vaccination, could However, there are several promising through indirect protection resulting from lead to differential effects if targeted to next-generation conjugate vaccines in reduced exposure to the infection in the certain population groups. For example, development, including two vaccine unvaccinated (herd ). if a resistant strain of a given pathogen candidates having received licensure in transmits preferentially in hospitals India. 9 Gavi, the Vaccine Alliance, has Pathway 2: Bystander effects (where antibiotic use is high), targeting opened a funding window for this vaccine, Any vaccines that lead to changes in the hospital population with a vaccine which will help increase access to these antibiotic use could potentially have could have a greater overall effect on vaccines in LMICs. an impact on AMR in organisms

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Escherichia coli severe AMR problems. Yet, with the article, AMR reduction is a key benefit of exception of P. aeruginosa, there is little vaccines but a recent review of published Infections caused by E. coli are activity in developing vaccines or other models of the impact of vaccines on the a major cause of morbidity and for these pathogens that dynamics of AMR did not find any studies associated antibiotic use. In particular, has extended beyond animal models and that considered the economic value of enterotoxigenic E. coli (ETEC) is a it is thought unlikely that these vaccines this benefit. 4 leading cause of diarrhoea in children will be available within the next 10 years. in developing countries. Ciprofloxacin- Major technical hurdles to developing The simplest way to estimate the benefit resistant ETEC strains represent a major vaccines for these “ESKAPE” pathogens of vaccines that prevent AMR is to challenge for ETEC treatment strategies exist such as limited understanding multiply the reduction in risk of acquiring in some parts of the world. While there of pathogen biology including natural a resistant strain in vaccinated individuals are no licensed vaccines for ETEC, immunity, limited knowledge of vaccine with the health detriment and financial vaccine development for ETEC is a WHO targets, the existence of multiple strains cost of being infected with such a strain. priority. There are a number of ETEC and a complex epidemiology where However, there are several reasons why vaccine candidates in development and resistance determinants frequently this approach may be too limited. First, currently undergoing phase II trials. move between different bacterial strains as discussed, there are several other The introduction of an ETEC vaccine and species. pathways by which vaccines can combat could play an important role in reducing AMR, including herd immunity, bystander resistance primarily through its impact on Viral infections effects, infection severity effects, subtype reduced antibiotic consumption but also effects, interspecific effects, and selective through reduced bystander selection. Respiratory syncytial virus (RSV) is targeting effects. Therefore, the benefit a common virus that can cause cold- of vaccination must be measured taking like symptoms in adults and is also account of these pathways. Second, several the causative agent for bronchiolitis reviews have highlighted how the wider in children. There is no licensed RSV AMR benefits of vaccination on households vaccine, but a number are undergoing and economies are often overlooked. 14 clinical trials, including vaccines that does not respect The economic cost of AMR is substantial are likely to be optimal for the paediatric when considering reductions in labour population as well as some that are likely borders, and productivity, the need to fund research into to be appropriate for pregnant women and developing new antimicrobials, and the older people. Viruses are also responsible many implications of potentially being unable for many diarrhoeal illness, and vaccines to perform routine medical procedures against these viruses may also lead to countries will such as surgery because of untreatable reductions in antibiotic use and reduced surgical site infections. 15 Finally, it is resistance by altering bystander selection. simultaneously important to consider the global nature of For example, the well-established the benefits of vaccines that prevent AMR. vaccines protect against the most common benefit from AMR does not respect borders, and many cause of severe diarrhoea in young ‘‘ countries will simultaneously benefit children and can prevent up to a third effective from effective vaccines. Economic models of severe diarrhoea cases in developing rarely consider this , which may countries. 11 Finally, a vaccine against vaccines discourage manufacturers from developing is a priority for development. vaccines. This market failure could be Health care associated infections Norovirus accounts for nearly 20% of addressed through mechanisms like all cases of acute gastroenteritis. 12 Two Multi-resistant health care associated advanced market commitments and market candidate vaccines have reached clinical infections are a common issue across all entry rewards, which have effectively trials and there are a number of candidates health care systems. They are particularly been utilised by Gavi and others for at preclinical development stages. 13 prevalent in hospital settings, where pneumococcal vaccines. antibiotics exert high selection pressure. Quantifying the economic benefit of Vaccines against some of these infections Access to vaccines are in development. For example, there vaccines that prevent antimicrobial are ongoing phase II/III clinical trials for resistance Positively, there has been growing Staphylococcus aureus and Pseudomonas attention to the role of vaccines in The value for money of a vaccination aeruginosa, which are opportunistic reducing the health burden of infectious programme can be estimated using an infections that are common causes of skin, and combating AMR. The result economic evaluation such as a cost– respiratory and urinary tract infections. 10 is a promising vaccine development effectiveness analysis, which considers The “ESKAPE” pathogens (Enterococcus, pipeline. However, there are concerns the balance between the incremental costs Klebsiella, Acinetobacter, Enterobacter) regarding the prices of vaccines and and incremental health impacts of an are responsible for some of the most the subsequent implications for equity intervention. As discussed throughout this

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of access, particularly in LMICs. The models that capture both direct and 8 Anwar E, Goldberg E, Fraser A, et al. Vaccines for cost of fully vaccinating a child with indirect effects of vaccines. Finally, the preventing typhoid fever. Cochrane Database Syst Rev all WHO recommended vaccines has economic pathway, which governs the 2014;1:CD001261. risen from $0.67 in 2001 to $45.59 value of reduced AMR. This will make use 9 Meiring JE, Gibani M, TyVAC Consortium Meeting in 2014. 16 There was also a 12-year gap of macroeconomic models which explore Group. The Typhoid Vaccine Acceleration Consortium between the first high-income country the long-term consequences of alternative (TyVAC): Vaccine effectiveness study designs: accelerating the introduction of typhoid conjugate introduction of hepatitis B vaccines and resistance rates on labour productivity, vaccines and reducing the global burden of enteric the first introduction in a low-income the need to continuously develop new fever. Report from a meeting held on 26–27 October country. 17 Gavi was set up in 2000 as a antibiotics and antibiotic classes, as well as 2016, Oxford, UK. Vaccine 2017;35(38):5081–8. public–private partnership in order to the wider health-system effects. 10 Czaplewski L, Bax R, Clokie M, et al. Alternatives address this access gap. However, most to antibiotics – a pipeline portfolio review. Lancet middle-income countries, including some References Infect Dis 2016;16(2):239–51. of the highest users of antibiotics, are not 11 Soares-Weiser K, Maclehose H, Bergman H, 1 Jit M, Cooper B. Chapter 8: The role of eligible. Vaccine purchasers in middle- et al. Vaccines for preventing rotavirus diarrhoea: vaccines in combating antimicrobial resistance. in income countries need strong economic Vaccines in use. Cochrane Database Syst Rev Anderson M, Cecchini M, Mossialos E. Challenges 2012;2:CD008521. rationales to introduce new vaccines in the in Tackling Antimicrobial Resistance: Economic and face of many competing health priorities. Policy Challenges. European Observatory on Health 12 Ahmed SM, Hall AJ, Robinson AE, et al. Global Hence, establishing the value proposition Systems and Policies Series. Cambridge University of norovirus in cases of gastroenteritis: for vaccine development and use has Press, 2019. A systematic review and meta-analysis. Lancet Infect Dis 2014 14(8):725–30. become increasingly important. 2 Hausdorff WP, Bryant J, Paradiso PR, et al. Which pneumococcal serogroups cause the 13 Cortes-Penfield NW, Ramani S, Estes MK, et al. most invasive disease: implications for conjugate Prospects and challenges in the development of a Conclusions vaccine formulation and use, part I. Clin Infect Dis Norovirus vaccine. Clin Ther 2017;39(8):1537–49. 2000;30(1):100–21. Vaccines are crucial to combating AMR. 14 Jit M, Hutubessy R, Png ME, et al. The broader However, when quantifying the economic 3 Lipsitch M, Siber G. How can vaccines contribute economic impact of vaccination: reviewing and benefit of vaccines, their impact on AMR to solving the antimicrobial resistance problem? appraising the strength of evidence. BMC Medicine mBio 2016;7(3):e00428. 2015;13:209. is often ignored. Adequately valuing this benefit is important in prioritising 4 Atkins KE, Lafferty EI, Deeny SR, et al. Use of 15 Jit M, Ng DHL, Luangasanatip N, Sandmann F, the vaccine development pipeline, as mathematical modelling to assess the impact of et al. Quantifying the economic cost of antibiotic vaccines on antibiotic resistance. Lancet Infect Dis resistance and the impact of related interventions: well as choosing between alternative 2018;18(6):e204–13. rapid methodological review, conceptual framework interventions (such as a new vaccine and a and recommendations for future studies. BMC Med 5 Kyaw MH, Lynfield R, Schaffner W, et al.. Effect of new antibiotic). To fully capture the value 2020;18(1):38. introduction of the pneumococcal conjugate vaccine of vaccines in reducing AMR, three sets on drug-resistant . New 16 Médecins Sans Frontières The right shot: bringing of pathways need to be quantified. First, Engl J Med 2006;354(14):1455–63. down barriers to affordable and adapted vaccines, the health system pathway, which governs 2nd edn. Geneva: MSF, 2015. Available at: https:// 6 Kwong JC, Maaten S, Upshur RE, et al. The effect msfaccess.org/right-shot-bringing-down-barriers- the impact of vaccines on antimicrobial of universal influenza on antibiotic affordable-and-adapted-vaccines-2nd-ed-2015 prescriptions. This will require clinical prescriptions: an ecological study. Clin Infect Dis trial and surveillance data on antimicrobial 2009;49(5):750–56. 17 GAVI Alliance Investing in immunisation through the GAVI Alliance – The evidence base. Geneva: GAVI prescription rates. Second, the 7 Azman AS, Parker LA, Rumunu J, et al. Alliance, 2012. Available at: https://www.gavi.org/ epidemiological pathway, which governs Effectiveness of one dose of oral cholera vaccine in library/publications/the-evidence-base/investing- response to an outbreak: A case-cohort study. Lancet the impact of vaccines on AMR (both in-immunisation-through-the-gavi-alliance—-the- Glob Health 2016;4(11):e856–63. directly and through reduced prescribing). evidence-base/

This will require dynamic transmission Cover_PB32.qxp_Cover _policy_brief 06/02/ 2019 10:55 Page 1

World Health Organization Regional Office for Europe UN City, Marmorvej 51, DK-2100 Copenhagen Ø, Denmark Tel.: +45 39 17 17 17 Fax: +45 39 17 18 18 E-mail: [email protected] web site: www.euro.who.int

HEALTH SYSTEMS AND POLICY ANALYSIS the brief aims to support the The European Observatory on Healt partnership that supports and prom h Systems and Policies Averting the AMR crisispolicy-making through comprehens otes evidence-based healthis a health systems in the European Region.ive and It rigorous analysis of range of policy-makers, academ brings together a wide POLICY BRIEF 32 implementation of national trends in health reform, drawingics on and exper practitioners to analyse Europe to illuminate policy is ience from across are available on its web site (http://www.healthobssues. The Observatory’s products ervatory.eu). Averting the AMR crisis action plans on AMR, drawing By: M Anderson, C Clift, Kai Schulze, et al. What are the avenues for policy action for countries in Europe? on numerous examples of

Michael Anderson Observatory Policy Brief 32 Charles Clift effective policies implemented Kai Schulze Anna Sagan Saskia Nahrgang by European Union Member Freely available for download: http://www.euro.who.int/__ Driss Ait Ouakrim Elias Mossialos States and involving the human, data/assets/pdf_file/0005/397652/PolicyBrief_PB32_FINAL_ In support of the Romanian Council Presidency animal and environmental WEB.pdf?ua=1 health sectors. ISSN 1997–8065

FcaUb]UbDfYg]XYbWm cZh\Y7cibW]`cZh\Y9 This policy brief summarises some of the key policy avenues ifcdYUbIb]cb for tackling antimicrobial resistance (AMR). Following the widely accepted ‘One Health’ approach to combating AMR,

Eurohealth — Vol.26 | No.1 | 2020