Kim, Jerome H

Marks, Florian

English

Apollo (Cambridge)

T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 381;23 nejm.org December 5, 20192262fractures. Considering the nearly equal risk of secondary surgical procedures and the modest benefit in functional outcome, should we aban-don the use of total hip arthroplasty in the treat-ment of hip fractures? Even if the benefits seem smaller than we previously thought, patients with high physical demands and a long remaining life expectancy should probably still be consid-ered for treatment with total hip arthroplasty. Yet the expected remaining lifetime of those pa-tients who potentially could benefit most from a total hip arthroplasty is much longer than the 2-year follow-up period used in the HEALTH trial. However, the number of secondary procedures after hemiarthroplasty may increase with longer follow-up. Therefore, one hopes that the HEALTH investigators will be able to provide long-term results from their trial in the future. Such data would be an even more important contribution to the knowledge base that supports hip-fracture treatment. There is still a need for large random-ized, controlled trials or registry-based random-ized clinical trials with greater numbers of pa-tients in order to identify how factors such as patient activity level, biologic age, and remain-ing life expectancy influence the risk of second-ary surgical procedures and functional outcome after hemiarthroplasty and total hip arthroplas-ty. Until then, in light of the results of the trial by Bhandari et al., we should probably be restric-tive in the selection criteria for total hip arthro-plasty for patients with hip fractures.Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org.From the Department of Orthopedic Surgery, Haukeland Uni-versity Hospital, and the Institute of Clinical Medicine, Univer-sity of Bergen — both in Bergen, Norway. 1. Parker M, Johansen A. Hip fracture. BMJ 2006; 333: 27-30.2. Hip fracture: management. Clinical guideline CG124. Lon-don: National Institute for Health and Clinical Excellence, June 2011 (https://www .nice .org .uk/ Guidance/ CG124).3. Management of hip fractures in the elderly: summary. Rose-mont, IL: American Academy of Orthopedic Surgeons, 2019 (https://www .aaos .org/ cc_files/ aaosorg/ research/ guidelines/ hipfxsummaryofrecommendations .pdf).4. Hopley C, Stengel D, Ekkernkamp A, Wich M. Primary total hip arthroplasty versus hemiarthroplasty for displaced intracap-sular hip fractures in older patients: systematic review. BMJ 2010; 340: c2332.5. Burgers PTPW, Van Geene AR, Van den Bekerom MPJ, et al. Total hip arthroplasty versus hemiarthroplasty for displaced femo-ral neck fractures in the healthy elderly: a meta-analysis and sys-tematic review of randomized trials. Int Orthop 2012; 36: 1549-60.6. Lewis DP, Wæver D, Thorninger R, Donnelly WJ. Hemiar-throplasty vs total hip arthroplasty for the management of dis-placed neck of femur fractures: a systematic review and meta-analysis. J Arthroplasty 2019; 34(8): 1837-1843.e2.7. The HEALTH Investigators. Total hip arthroplasty or hemi-arthroplasty for hip fracture. N Engl J Med 2019; 381: 2199-208.8. Tsikandylakis G, Mohaddes M, Cnudde P, Eskelinen A, Kär-rholm J, Rolfson O. Head size in primary total hip arthroplasty. EFORT Open Rev 2018; 3: 225-31.9. Jobory A, Kärrholm J, Overgaard S, et al. Reduced revision risk for dual-mobility cup in total hip replacement due to hip fracture: a matched-pair analysis of 9,040 cases from the Nordic Arthroplasty Register Association (NARA). J Bone Joint Surg Am 2019; 101: 1278-85. 10. Hip, knee & shoulder arthroplasty: 2019 annual report. Ad-elaide, SA: Australian Orthopaedic Association National Joint Replacement Registry, 2019.DOI: 10.1056/NEJMe1913800Copyright © 2019 Massachusetts Medical Society.Parting the Clouds over Typhoid with a New Conjugate VaccineFlorian Marks, Ph.D., and Jerome H. Kim, M.D.Typhoid fever is caused by fecal–oral transmis-sion of Salmonella enterica serovar Typhi (S. Typhi). It has been a deadly companion to mankind for centuries, affecting 10.9 million persons and re-sulting in an estimated 116,800 deaths per year.1 Although vaccines against typhoid have been avail-able for more than a century and have been shown to be protective,2,3 the approved vaccines (inject-able Vi polysaccharide and oral, live-attenuated Ty21a typhoid vaccines) have not been useful in populations with a high typhoid burden, particu-larly in young children.4 To address this shortfall, the Bill and Melinda Gates Foundation, as well as other donors, has supported the development of new typhoid conjugate vaccines (TCVs), generated data on disease burden, and coordinated with international stakeholders to introduce the vac-cine in countries where typhoid fever is endemic.Typbar-TCV was developed by Bharat Biotech International in India and was prequalified by the World Health Organization (WHO)3 on the basis of immunogenicity and evidence of protec-tion (55% efficacy) in a typhoid human challenge model.5 In this issue of the Journal, Shakya et al.6 report that this vaccine was immunogenic and efficacious against blood culture–confirmed ty-Editorialsn engl j med 381;23 nejm.org December 5, 2019 2263phoid fever, with an estimated vaccine efficacy of 81.6% at 12 months, in a trial involving chil-dren who were between 9 months and 16 years of age.Data from African and Asian surveillance studies were used by the WHO Strategic Advi-sory Group of Experts to recommend the use of TCVs in countries where typhoid fever is en-demic.2,4 Subsequently, TCVs were added to vac-cines subsidized by Gavi, the Vaccine Alliance. The Typbar-TCV vaccine is already commercially available in India. Other large studies, such as the TCV introduction program in Navi Mumbai, India (ClinicalTrials.gov number, NCT03554213), are currently ongoing,7 and introduction of the vaccine through Gavi subsidies in Asian and African countries is also under way. Ongoing and planned clinical trials are geared toward systematic assessment of vaccine performance and addressing unanswered scientific questions regarding effectiveness, herd immunity, cost-effectiveness, and the effect of the vaccine on antimicrobial resistance. The trial by Shakya and colleagues, combined with evidence of safety and immunogenicity in other trials,7 provides support for broader introduction of TCVs in coun-tries where typhoid is endemic. The national and international stakeholders involved in decisions regarding the introduction of TCV await results from longer-term follow-up to determine wheth-er protection elicited by TCVs exceeds that of existing Vi polysaccharide and live-attenuated oral vaccines.Typhoid fever has been successfully treated with antimicrobial agents since early in the anti-microbial era, but sustained antibiotic pressure through large-scale (over)use has created multi-drug-resistant and extensively drug-resistant (XDR) typhoid strains that have spread in India, Bangladesh, and Pakistan.8 Patients with severe S. Typhi infection caused by a resistant strain often have prolonged hospital stays and limited treatment options. Moreover, the presenting signs and symptoms of typhoid fever are nonspecific, and diagnostic testing is hampered by the poor sensitivity and limited availability of existing tests, including blood cultures (which, although insensitive, are considered to be the best avail-able test for typhoid fever), particularly in resource-limited areas. Thus, patients with suspected ty-phoid fever in areas where typhoid is endemic frequently receive antimicrobial agents from health care providers, and unnecessary antimicrobial pressure is added to resident bacterial popula-tions. To date, XDR typhoid is confined to India, Bangladesh, and Pakistan, where newer antibiot-ics are available.8 Yet, it is easy to envision that the introduction of XDR S. Typhi strains into Africa, with underresourced health care systems and a lack of treatment options, could lead to a scenario involving considerable morbidity and mortality.Additional large-scale trials are under way to provide data on vaccine performance in other geographic areas. The Typhoid Vaccine Accelera-tion Consortium (TyVAC) is evaluating TCV in Dhaka, Bangladesh (in a cluster-randomized tri-al), Blantyre, Malawi (in an individually random-ized trial), and Ouagadougou, Burkina Faso (in coadministration studies).9 Researchers in the THECA (Effect of a Novel Typhoid Conjugate Vaccine in Africa: A Multicenter Study in Ghana and the Democratic Republic of the Congo) trial are in close alignment with the TyVAC, conduct-ing a cluster-randomized trial in Agogo, Ghana, and a large-scale trial of vaccine effectiveness in Kisantu, Democratic Republic of Congo.10 This compendium of data for stakeholders in the in-troduction of vaccine may be used to target in-terventions to protect as many persons as pos-sible given the existing constraints on resources.Shakya and colleagues have made an impor-tant contribution to the global fight against S. Typhi infection, but global health is about im-pact. If further studies support and extend these results, how can a corresponding reduction in the burden of typhoid disease and death be achieved most efficiently?Disclosure forms provided by the authors are available with the full text of this editorial at NEJM.org.From the International Vaccine Institute, Seoul, South Korea (F.M., J.H.K.); and the University of Cambridge, Cambridge, United Kingdom (F.M.). 1. GBD 2017 Typhoid and Paratyphoid Collaborators. The glob-al burden of typhoid and paratyphoid fevers: a systematic analy-sis for the Global Burden of Disease Study 2017. Lancet Infect Dis 2019; 19: 369-81 2. World Health Organization. Meeting of the strategic Advi-sory Group of Experts on immunization, October 2017 — con-clusions and recommendations. Wkly Epidemiol Rec 2017; 92: 729-473. World Health Organization. Typhoid vaccine prequalified. January 3, 2019 (http://www .who .int/ medicines/ news/ 2017/ WHOprequalifies - breakthrough - typhoid - vaccine/ en/ ).4. World Health Organization. Typhoid vaccines: WHO posi-tion paper, March 2018 — recommendations. Vaccine 2019; 37: 214-6.Editorialsn engl j med 381;23 nejm.org December 5, 201922645. Jin C, Gibani MM, Moore M, et al. Efficacy and immunoge-nicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet 2017; 390: 2472-80.6. Shakya M, Colin-Jones R, Theiss-Nyland K, et al. Phase 3 efficacy analysis of a typhoid conjugate vaccine trial in Nepal. N Engl J Med 2019; 381: 2209-18.7. World Health Organization. Global Advisory Committee on Vaccine Safety, 5–6 December 2018. Wkly Epidemiol Rec 2019; 4: 45-52.8. Levine MM, Simon R. The gathering storm: is untreatable typhoid fever on the way? MBio 2018; 9(2): e00482-e18.9. Meiring JE, Gibani M. The Typhoid Vaccine Acceleration Consortium (TyVAC): vaccine effectiveness study designs: accel-erating the introduction of typhoid conjugate vaccines and re-ducing the global burden of enteric fever — report from a meet-ing held on 26-27 October 2016, Oxford, UK. Vaccine 2017; 35: 5081-8 10. European & Developing Countries Clinical Trials Partner-ship (EDCTP). Effect of a novel typhoid conjugate vaccine in Africa: a multicentre study in Ghana and the Democratic Re-public of the Congo (http://www .edctp .org/ projects - 2/ edctp2 - projects/ strategic - actions - supporting - large - scale - clinical - trials - 2017/ ).DOI: 10.1056/NEJMe1914695Copyright © 2019 Massachusetts Medical Society.

Parting the Clouds over Typhoid with a New Conjugate Vaccine.

https://www.repository.cam.ac.uk/bitstream/1810/309493/1/NEJM.pdf

Parting the Clouds over Typhoid with a New Conjugate Vaccine.

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