Deploy Vaccines to Fight Superbugs

PROGRAM ON THE GLOBAL DEMOGRAPHY OF AGING AT HARVARD UNIVERSITY

Working Paper Series

Rino Rappuoli, David E. Bloom, and Steve Black

December 2017

PGDA Working Paper No. 142 http://www.hsph.harvard.edu/pgda/working/

Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Number P30AG024409. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. COMMENT WEATHER Research must HEALTH How people with MEDICINE Sanctions leave long OBITUARY Ronald Breslow, adapt to the demands Lyme disease were shadow for users of blood- pioneering organic chemist, of society p.168 finally vindicated p.174 clotting factor in Iran p.175 remembered p.176 EDUARDO SOTERAS/AFP/GETTY EDUARDO

Vaccines can have an effect on antimicrobial resistance by reducing the number of ill people and avoiding unnecessary antibiotic prescriptions. Deploy vaccines to fight superbugs Immunizations combined with antibiotics could be our best shot at combating drug-resistant microbes, argue Rino Rappuoli, David E. Bloom and Steve Black.

acteria, viruses, parasites and fungi Antimicrobials alone won’t be able to stakeholders need to see antibiotics and that are resistant to drugs cause mitigate the threat. The supply of naturally vaccines as complementary tools. Here we 700,000 deaths each year. By 2050, such occurring antibiotics seems thin. And efforts focus on antibiotic-resistant bacteria, for B‘superbugs’, inured to treatments, could cause to engineer new ones have floundered. which the need for solutions is most urgent. up to 10 million deaths annually and cost the We think that vaccines could be a key global economy US$100 trillion1–2. If this hap- way to stem the crisis. To launch a global INFECTION RISK pens, antimicrobial resistance (AMR) will be strategic effort to prioritize their develop- Unchecked, AMR could substantially limit a bigger killer than cancer is now. ment, scientists, policymakers and key our ability to conduct routine surgery,

COMMENT

chemotherapy and transplantation and return us to a world in which infectious VACCINES IN THE LEAD diseases drastically shorten lives. Strains of Since the 1980s, 22 vaccines have been deployed in the clinic, but no truly new class of antibiotics has been discovered or engineered. many pathogenic bacteria, such as Neisseria 71–109 (2011). 24, gonorrhoeae and Staphylococcus aureus, are 8 already resistant to most antibiotics. Antibiotics The genes conferring AMR are often Vaccines Various advances in molecular carried in plasmids: small, circular pieces 6 3 biology have of DNA that bacteria exchange easily spurred vaccine through a process called horizontal gene development. CLIN. MICROBIOL. REV. transfer. Genes from many plasmids can 4 COMPILED DATA 889–893 (2011); ANTIBIOTICS 9, even combine into one unit that renders . bacteria resistant to most antibiotics in a Number developed single step. 2 FROM L. SILVER Between 1950 and 1980, new antibiotics reached the clinic with regularity. But

the pipeline has run dry. No truly new ones & S. L. PLOTKIN COMPILED FROM S. A. PLOTKIN DATA VACCINES SOURCES:

0 MICROBIOL REV. NATURE active against a wide range of pathogenic 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 bacteria have been deployed in the clinic in three decades. Antibiotics need to reach targets that are usually behind the bacte- elements to create new synthetic sequences Some, such as the pneumococcal vaccine, rial cell wall — a formidable barrier — and that would not otherwise occur. Conjugate do so directly by reducing the carriage and avoid being ejected by potent efflux pumps. vaccines have drastically reduced the inci- transmission of antibiotic-resistant bacte- These challenges continue to hamper clinical dence of meningitis caused by Haemophilus ria9. Others do so indirectly. The influenza development despite numerous technologi- influenzae, pneumococcus (Streptococcus vaccine, for instance, cuts the incidence of cal advances, from new ways to construct and pneumoniae) and meningococcus (Neisseria fevers, and so minimizes the number of anti- modify molecules to genomics. meningitidis). These are produced by making biotic doses that are needlessly prescribed The story is much more encouraging covalent links between bacterial polysaccha- and taken10. for vaccines. They almost never prompt rides and proteins. We call for a global strategic effort to bacteria to develop resistance4. Antibiot- More recently, reverse vaccinology led to develop a portfolio of vaccines that target ics are generally prescribed after a person a vaccine against meningococcus B (ref. 6). AMR. Launching this will require policy- has become infected and has hundreds of In this approach, researchers mine the thou- makers and stakeholders to make advances millions or billions of bacteria in their body. sands of proteins encoded by bacterial genes on three fronts. One bacterium in a billion can acquire the in search of possible vaccine candidates, Economics. If current methods were ability to thrive in the presence of antibiot- such as proteins that are exposed on the used to calculate the economic value of ics through a spontaneous mutation or by cell surface. Reverse vaccinology could also vaccines, many of those targeting resist- obtaining a plasmid encoding resistance identify sequences that are unique to patho- ant bacteria would not be deemed cost- genes. With vaccines, by contrast, the host genic microorganisms. This could prevent effective because the effects on AMR are builds immunity before encountering the investigators from producing vaccines that not factored in. To persuade governments pathogen, and bacteria are neutralized at accidentally harm beneficial commensal and drug companies to invest in vaccines, the beginning of the infection, when they microbes, such as those in the gut7. health economists must model the incre- number only a few hundred or thousand. Finally, work on potent and safe new mental cost of AMR and count the avoid- Thus one-in-a-billion genetic events are adjuvants — compounds that make vac- ance of that cost as a benefit of vaccine much less likely. cines more effective — has achieved some development and use. Furthermore, most antibiotics consist of impressive feats. These include a malaria Awareness. Recent discussions with the a single compound. Vaccines — which can vaccine, and a herpes zoster vaccine licensed UK Wellcome Trust, the Bill & Melinda contain entire bacteria or viruses, or several by the US Food and Drug Administration Gates Foundation and the US National antigens — usually induce immunity against just two months ago. This vaccine induces Institutes of Health suggest that all these multiple targets. This makes the develop- a potent immune response against the virus organizations recognize vaccines as impor- ment of resistance even harder. that causes shingles, even in people aged tant tools in the fight against AMR. Yet the In other words, vaccines seem to be almost 80 or older5,8. reports and mission statements of manu- evolution-proof 4. Diphtheria and tetanus Vaccine technologies continue to evolve. facturers and of policymakers, such as the vaccines, for example, have been used for For example, scientists are analysing the World Health Organization (WHO) and the 70 years or more without generating resist- atomic structure of antigens with a view United Nations General Assembly (UNGA), ance. Likewise, by 1980 the smallpox vaccine to modifying them to make them more indicate that most key players see AMR as a had eradicated the naturally circulating virus effective as vaccines. Progress in immunol- problem that needs to be addressed primar- worldwide without generating resistance. ogy and synthetic biology, too, are likely to ily through stewardship and the develop- Vaccines have also proved more ‘discov- make it possible for researchers to tackle ment of new antibiotics. erable’ than antibiotics5. Since the 1980s, diseases that have so far remained out of To change mindsets, epidemiologists 22 vaccines have been developed thanks to reach, such as respiratory syncytial virus and need to mine the data and demonstrate various advances in molecular biology (see cytomegalovirus6. the impact existing vaccines already have ‘Vaccines in the lead’). Researchers produced on AMR (see ‘Resistance curbed’). They vaccines against hepatitis B and human pap- VACCINES FOR AMR also need work with economists to model illomavirus (which cause liver cancer and Antibiotics remain the only life-saving treat- the health and economic benefits of greater cervical cancer, respectively) using recom- ment for an acute bacterial infection. Yet investment in vaccines. This evidence must binant DNA technology. They fused genetic several vaccines already help to stem AMR. be communicated to policymakers and the

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public. (The growth of the anti-vaccine community in recent years is a signal that those of us who recognize the health benefits of vaccines need to do better at communicating them.) Meetings between scientists and stakeholders from both the vaccine and the antimicrobial communi- ties should be promoted and funded to PER-ANDERS PETTERSSON/GETTY PER-ANDERS enable discussion of an integrated strategy to target AMR. Prioritization and trial design. Policy- makers, funders and manufacturers must agree on what resistant strains to prioritize for vaccine development, depending on the threat they pose and the feasibility of vaccine development. The WHO and other key stakeholders, such as the US Centers for Disease Control and Prevention, that already make recommendations about which strains to prioritize in the hunt for antibiotics, could take the lead. Likewise, manufacturers of vaccines must begin discussions with regulators to establish which clinical-trial designs would demonstrate the effectiveness of vaccines targeting AMR. Also, the effects of vaccines on AMR should be included in the information leaf- lets that accompany them, to facilitate recommendations by agencies such as the UK Vaccines rarely prompt bacteria to develop resistance. Joint Committee on Vaccination and Immu- nisation and the US Advisory Committee on current antibiotic armament2. Lawmakers and professor of vaccines research at Immunization Practices. need to bring in more effective regulation Imperial College London, UK. David No single strategy will suffice when it to lessen the inappropriate use of drugs (for E. Bloom is professor of economics and comes to overcoming the challenges posed instance as growth promoters for livestock, demography at the Harvard T. H. Chan by drug-resistant pathogens. The use of anti- or as a result of people buying cheap drugs School of Public Health, Harvard biotics and vaccines must be accompanied on the black market in emerging econo- University, Boston, Massachusetts, USA. by improved diagnostics to allow caregivers mies). Also, shortcomings in health systems Steve Black is professor of paediatrics to make better use of the drugs we already worldwide (primarily, a lack of care givers at the Division of Infectious Diseases, have. Enhanced stewardship programmes who are sufficiently informed about when Cincinnati Children’s Hospital, Cincinnati, need to be developed, such as those involv- vaccinations or antibiotics are the best Ohio, USA. ing improvements to sanitation, to pre- course of treatment) could hamper vaccina- e-mails: [email protected]; vent the spread of infections. And better tion strategies, even when effective vaccines [email protected]; global surveillance of drug resistance is also are available. [email protected] required to preserve the effectiveness of our These weaknesses must be shored up, for 1. The Review on Antimicrobial Resistance. instance by overseas training programmes. Antimicrobial Resistance: Tackling A Crisis For The One example is the master’s in vaccinology Health And Wealth Of Nations (Wellcome Trust at the University of Siena in Italy, which and UK Government, 2014). RESISTANCE CURBED 2. The Review on Antimicrobial Resistance. Tackling The number of two-year-olds in South Africa trains visiting physicians from low-income Drug-Resistant Infections Globally: Final Report with resistant strains of pneumococcus fell countries in vaccine development and and Recommendations (Wellcome Trust and UK after pneumococcal conjugate vaccine (PCV) Government, 2016). was introduced. implementation, enabling them to apply this knowledge when they return to their 3. Falkow, S. Infectious Multiple Drug Resistance Penicillin Multidrug resistance (Pion, 1975). Ceftriaxone home countries. 4. Kennedy, D. A. & Read, A. F. Proc. Biol. Sci. 284, 40 Over the past few years, key institutional 20162562 (2017). 5. Rappuoli, R., Pizza, M., Del Giudice, G. & PCV is stakeholders — notably the WHO, the introduced De Gregorio, E. Proc. Natl Acad. Sci. USA 111, UNGA, the World Bank, the G20 group 12288–12293 (2014). SOURCE: REF. 9 SUPPLEMENTARY MATERIAL 9 SUPPLEMENTARY SOURCE: REF. 30 of countries, the European Union and the 6. Rappuoli, R., Bottomley, M. J., D’Oro, U., Finco, O. & De Gregorio, E. J. Exp. Med. 213, 469–481 UK and US governments — have called (2016). for researchers to develop new antibiotics 7. Moriel, D. G. et al. MBio 3, e00118–12 (2012). 20 to expand our arsenal in the war against 8. Cunningham, A. L. et al. N. Engl. J. Med. 375, superbugs. We appeal to these organizations 1019–1032 (2016). 9. von Gottberg, A. et al. N. Engl. J. Med. 371, to call now for a multi-layered strategy that 10 1889–1899 (2014). prioritizes the development of vaccines to 10. Kwong, J. C., Maaten, S., Upshur, R. E., target resistant strains. ■ Patrick, D. M. & Marra, F. Clin. Infect Dis. 49,

Number of cases per 100,000 people 750–756 (2009). 0 2006 2008 2010 2012 Rino Rappuoli is chief scientist at R.R. declares competing financial interests; see GlaxoSmithKline Vaccines, Siena, Italy; go.nature.com/2btnst9.

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