Modelling the value of vaccines in reducing the burden of antimicrobial resistance
Contact: [email protected]
Antimicrobial resistance (AMR) is a global issue with increasingly severe consequences for the world economy and human health. The use of vaccines has been shown empirically to reduce AMR1, however, the benefits of vaccination campaigns in reducing AMR infections and improving health and economic outcomes have yet to be extensively quantified. Measuring these benefits is essential for public health planning, particularly as the costs associated with new vaccines increase, economic analysis is needed to justify the expenditure in different health contexts.
ARVac, a consortium including CDDEP, Yale, Berkeley, Imperial College London, and Princeton, is at the cutting edge of infectious disease modeling to assess the health and economic impact avertable by potential, new, or current vaccines targeting Typhoid, shigella, Streptococcus pneumoniae, rotavirus, respiratory syncytial virus, or tuberculosis (TB). Monoclonal antibodies that target Gram-negative organisms causing neonatal sepsis will also be included in the analysis. The project brings together a consortium of modelers who are experts in each of the disease areas from Yale, Berkeley, Imperial College London, Princeton, and CDDEP. The key outputs will be reductions in resistant infections, deaths, years of life lost and antibiotic consumption due to vaccination, and the associated economic outcomes.
This work is as part of a broader collaboration between CDDEP, World Health Organization (WHO), the Bill & Melinda Gates Foundation (BMGF), and the Wellcome Trust which aims to better define the role of vaccines against AMR and determine the priorities for strengthening the impact of vaccines against AMR.
Vaccines can reduce AMR via two mechanisms: (1) a lower overall burden of infection leads to a reduction in the transmission of resistant and susceptible pathogens; (2) fewer infections mean less need to consume antibiotics, thereby lessening the selection pressure for resistant pathogenic strains (Figure 1). Ultimately, this reduction in resistant cases will lead to fewer untreatable infections and more lives saved. These relationships are complex, however, and more in-depth analyses of the different contributing factors have been described elsewhere2.
In general, efforts to assess the benefits of vaccines in terms of deaths averted and reductions in medical impoverishment have not considered the effects on AMR3. Many vaccines, both those in current use and those in the pipeline, have the potential to help reduce the AMR disease burden and thereby save lives.
Pneumococcal disease is a cause of pneumonia, invasive disease, ear infections, and sinus infections and results in 1.6 million deaths annually 4. Treatment is becoming more complicated due to emerging resistance however there is extensive evidence that pneumococcal conjugate vaccine (PCV) has reduced resistant infections1,5,6. PCV has also been shown to reduce antibiotic consumption7,8. In the US alone it has been predicted that PCV-7 has the potential to prevent 1.4 million antibiotic prescriptions each year9. Other research suggests PCV could reduce the amount of antibiotics used to treat pneumonia by 47%, this is the equivalent of 11.4 million antibiotic days globally 10.
Seasonal influenza causes 1 billion cases of infection11and 650,000 deaths every year12. Influenza infections can lead to secondary bacterial infections requiring antibiotic 13however often antibiotic prescribing associated with influenza is inappropriate 6. 22% of influenza subjects in the US were prescribed antibiotics, despite the fact that 79% of them had no evidence of a secondary infection or comorbidity14. Evidence suggests vaccination reduces such usage15.
Tuberculosis (TB) claims more lives than any other pathogen worldwide16. The number of TB cases resistant to treatment is increasing and making treatment more difficult and prolonged16. Though bacillus Calmette–Guérin (BCG) vaccine was introduced in the 1920s new more effective vaccines are needed and there are multiple candidates in the pipeline16. Vaccines are likely to be a useful tool against drug resistant-TB, which can take up to two years to treat and have a high treatment cost relative to susceptible TB17.
21 million cases of typhoid and 222,000 typhoid-related deaths occur every year globally 18. Typhoid fever is caused by SalmonellaTyphi which is becoming increasingly difficult to treat due to emerging resistance19,20. Typhoid conjugate vaccine was prequalified by WHO in 2018 and is now being introduced across parts of the developing world21–23.
Shigella causes 165 million cases of dysentery annually worldwide, mainly in children under five living in developing countries24. Antibiotic resistance is increasingly prevalent, with deadly consequences25. Multiple vaccine candidates are currently undergoing evaluation though no approved vaccine yet exists26.
Rotaviruses are a common cause of severe diarrhea in young children27and associated with a large amount of antibiotic prescribing. Wider introduction of currently existing rotavirus vaccines has the potential to reduce antibiotic use and save lives 28.
Gram-negative Bacteria (monoclonal antibodies)
Drug-resistant Gram-negative bacteria, including Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenem-resistant Enterobacteriaceae, are a rising threat. Monoclonal antibodies are highly specific, have a limited risk of resistance development, and may work synergistically with antibiotics by directly targeting resistant strains29. It has been suggested that this alternative to antibiotics has low risk and high potential30.
 Birger R, Antillón M, Bilcke J, Dolecek C, Dougan G, Pollard AJ, Neuzil KM, Frost I, Laxminarayan R, Pitzer VE. (2022) ccccc: a mathematical modelling study. [Lancet Infect Dis]
 Fu H, Lewnard JA, Frost I, Laxminarayan R, Arinaminpathy N. (2021) Modelling the global burden of drug-resistant tuberculosis avertable by a post-exposure vaccine. [Nat Commun].
 Vekemans J, Hasso-Agopsowicz M, Kang G, Hausdorff WP, Fiore A, Tayler E, Klemm EJ, Laxminarayan R, Srikantiah P, Friede M, Lipsitch M. (2021) Leveraging Vaccines to Reduce Antibiotic Use and Prevent Antimicrobial Resistance: A World Health Organization Action Framework. [Clin Infect Dis]
 Andrejko K, Ratnasiri B, Hausdorff WP, Laxminarayan R, Lewnard JA. (2021) Antimicrobial resistance in paediatric Streptococcus pneumoniae isolates amid global implementation of pneumococcal conjugate vaccines: a systematic review and meta-regression analysis. [Lancet Microbe]
 Lewnard, J.A., Lo, N.C., Arinaminpathy, N., Frost, I, Laxminarayan, R., (2020) Childhood vaccines and antibiotic use in low- and middle-income countries. [Nature]
 Klein EY, Schueller E, Tseng KK, Morgan DJ, Laxminarayan R, Nandi A. The Impact of Influenza Vaccination on Antibiotic Use in the United States, 2010-2017. (2020) [Open Forum Infect Dis]
 Lewnard JA, Rogawski McQuade ET, Platts-Mills JA, Kotloff KL, Laxminarayan R. (2020) Incidence and etiology of clinically-attended, antibiotic-treated diarrhea among children under five years of age in low- and middle-income countries: Evidence from the Global Enteric Multicenter Study. (2020) [PLoS Negl Trop Dis]
1 Von Gottberg A, de Gouveia L, Tempia S, et al. Effects of Vaccination on Invasive Pneumococcal Disease in South Africa. N Engl J Med 2014; 371: 1889–99.
2 Atkins KE, Lafferty EI, Deeny SR, Davies NG, Robotham J V., Jit M. Use of mathematical modelling to assess the impact of vaccines on antibiotic resistance. Lancet Infect Dis 2017; 3099: 1–10.
3 Chang AY, Riumallo-Herl C, Perales NA, et al.The Equity Impact Vaccines May Have On Averting Deaths And Medical Impoverishment In Developing Countries. 2018. DOI:10.1377/hlthaff.2017.0861.
4 World Health Organization. WHO Pneumococcal Disease. http://www.who.int/ith/diseases/pneumococcal/en/ (accessed Feb 26, 2018).
5 Ginsburg AS, Klugman KP. Vaccination to reduce antimicrobial resistance. Lancet Glob Heal 2017; 5: e1176–7.
6 Orenstein WA, Gellin BG, Beigi RH, et al. A Call for Greater Consideration for the Role of Vaccines in National Strategies to Combat Antibiotic-Resistant Bacteria: Recommendations from the National Vaccine Advisory Committee. 2016 DOI:10.1177/003335491613100105.
7 Dagan R, Sikuler-Cohen M, Zamir O, Janco J, Givon-Lavi N, Fraser D. Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees. Pediatr Infect Dis J 2001; 20: 951–8.
8 Fireman B, Black S, Shinefield H, Lee J, Lewis E, Ray P. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J 2003; 22: 10–6.
9 Grijalva CG, Nuorti JP, Griffin MR. Antibiotic prescription rates for acute respiratory tract infections in US ambulatory settings. J Am Med Assoc 2009; 302: 758–66.
10 Laxminarayan R, Matsoso P, Pant S, Brower C, Røttingen, John-Arne Klugman K, Davies S. Access to effective antimicrobials: a worldwide challenge. Lancet 2016; 387: 168–75.
11 World Health Organization. WHO Influenza. http://www.who.int/immunization/topics/influenza/en/ (accessed Feb 24, 2018).
12 World Health Organization. Up to 650 000 people die of respiratory diseases linked to seasonal flu each year. http://www.who.int/mediacentre/news/releases/2017/seasonal-flu/en/ (accessed Feb 26, 2018).
13 Kash JC, Taubenberger JK. The role of viral, host, and secondary bacterial factors in influenza pathogenesis. Am J Pathol 2015; 185: 1528–36.
14 Misurski DA, Lipson DA, Changolkar AK. Inappropriate antibiotic prescribing in managed care subjects with influenza. Am J Manag Care 2011; 17: 601–8.
15 Hurwitz E, Haber M, Chang A, et al.Effectiveness of influenza vaccination of Day Care Children in Reducing Influenza-Related Morbidity Among Household Contacts. N Engl J Med 2007; 357: 2730–1.
16 WHO. Global Tuberculosis Report 2017. 2017 DOI:WHO/HTM/TB/2017.23.
17 Manjelievskaia J, Erck D, Piracha S, Schrager L. Drug-resistant TB: Deadly, costly and in need of a vaccine. Trans R Soc Trop Med Hyg 2015; 110: 186–91.
18 World Health Organization. WHO Typhoid. http://www.who.int/immunization/diseases/typhoid/en/ (accessed Feb 24, 2018).
19 Wong VK, Baker S, Pickard DJ, et al. Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter-and intracontinental transmission events. Nat Genet 2015; 47: 632–9.
20 Baumgaertner E. ‘We’re Out of Options’: Doctors Battle Drug-Resistant Typhoid Outbreak. New York Times. 2018.
21 WHO. Typhoid vaccine prequalified. 2018.
22 Reuters. Malawi is first African nation using new WHO approved typhoid vaccine. Africa News. 2018.
23 Mogasale V, Ramani E, Park IY, Lee JS. A forecast of typhoid conjugate vaccine introduction and demand in typhoid endemic low- and middle-income countries to support vaccine introduction policy and decisions. Hum Vaccines Immunother 2017; 13: 2017–24.
24 Dr P, Williams P, James AB. Dysentery (Shigellosis) Current Who Guidelines and the Who Essential Medicine List for Children. Who 2016; : 33.
25 World Health Organization. WHO Shigella. http://www.who.int/immunization/topics/shigella/en/ (accessed Feb 24, 2018).
26 World Health Organization. WHO’s 4th Product Development for Vaccines Advisory committee Meeting Executive Summary. 2017; : 1–4.
27 World Health Organization. WHO Rotavirus. http://www.who.int/immunization/topics/rotavirus/en/ (accessed Feb 24, 2018).
28 O’Neill J. Vaccines and alternative approaches: reducing our dependence on antimicrobials. Rev Antimicrob Resist 2016; : 36.
29 Lipsitch M, Siber GR. How can vaccines contribute to solving the antimicrobial resistance problem? MBio 2016; 7: 1–8.
30 Czaplewski L, Bax R, Clokie M, et al.Alternatives to antibiotics-a pipeline portfolio review. Lancet Infect Dis 2016; 16: 239–51.