with the once-weekly medication, would aﬀect glycaemic control in daily life is diﬃcult and needs further study. As for DPP-4 inhibitors, large, long-term prospective trials with cardiovascular outcomes are underway, comparing GLP-1 receptor agonists (either once-daily liraglutide or once-weekly GLP-1 receptor agonists, such as exenatide long-acting release, dulaglutide, semaglutide, and albiglutide) with placebo in patients with type 2 diabetes and a high cardiovascular risk proﬁle. Although none of these trials will provide headto-head comparisons, the data they will oﬀer to the medical community should help physicians in the best choice of incretin-based therapies for management of type 2 diabetes.
André J Scheen
University of Liège, Division of Diabetes, Nutrition and Metabolic Disorders and Clinical Pharmacology Unit, Department of Medicine, CHU Sart Tilman, B-4000 Liège, Belgium [email protected]
I have received lecture, adviser’s, or investigator’s fees from AstraZeneca/BMS, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanoﬁ-Aventis, and Takeda. 1
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696–705. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55: 1577–96.
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Scheen AJ, Radermecker RP. Addition of incretin therapy to metformin in type 2 diabetes. Lancet 2010; 375: 1410–12. Scheen AJ. GLP-1 receptor agonists or DPP-4 inhibitors: how to guide the clinician? Ann Endocrinol (Paris) 2013; 74: 515–22. Scheen AJ. Exenatide once weekly in type 2 diabetes. Lancet 2008; 372: 1197–98. Owens DR, Monnier L, Bolli GB. Diﬀerential eﬀects of GLP-1 receptor agonists on components of dysglycaemia in individuals with type 2 diabetes mellitus. Diabetes Metab 2013; 39: 485–96. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374: 39–47. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008; 372: 1240–50. Blevins T, Pullman J, Malloy J, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab 2011; 96: 1301–10. Wysham C, Blevins T, Arakaki R, et al. Eﬃcacy and safety of dulaglutide added on to pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care 2014; published online May 30. DOI:10.2337/dc13-2760. Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 2013; 381: 117–24. Pratley RE, Nauck MA, Barnett AH, et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol 2014; 2: 289–97. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet 2014; published online July 11. http://dx.doi.org/10.1016/S01406736(14)60976-4.
The need for a dengue vaccine is more pressing than ever. Dengue—a mosquito-borne viral infection caused by any of the four dengue virus serotypes— is regarded as the most important arboviral disease globally, because more than 50% of the world’s population live in regions at risk of the disease, and evidence points towards further geographical and numerical expansion.1 The results of Maria Capeding and colleagues’ multicentre phase 3, randomised, observer-masked, placebo-controlled eﬃcacy trial2 for a recombinant, chimeric, live attenuated tetravalent dengue vaccine (CYD-TDV), in The Lancet, have been awaited with great anticipation paired with some trepidation, on the basis of the disappointing results from a previous single-centre trial with the same vaccine in Thailand.3 www.thelancet.com Vol 384 October 11, 2014
Capeding and colleagues’ trial2 was done in ﬁve countries in the Asia-Paciﬁc region and assessed 10 275 healthy children aged 2–14 years. The primary objective was to estimate protective eﬃcacy against symptomatic, virologically conﬁrmed dengue after the completion of three doses of CYD-TDV given 6 months apart (at months 0, 6, and 12). The incidence density of virologically conﬁrmed dengue during the 25-month active surveillance phase was 1·8 % (95% CI 1·5–2·1) in the children in the vaccine group and 4·1% (3·5–4·9) in those in the control group, translating into an overall protective eﬃcacy of 56·5% (43·8–66·4). The overall vaccine eﬃcacy in the per-protocol analysis was similar to that in the intention-to-treat analysis (54·8% [46·8–61·7]). Eﬃcacy was serotype speciﬁc. Consistent with the previous single-centre, phase 2b trial in Thailand,3
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Dengue vaccines: dawning at last?
Published Online July 11, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)61142-9 See Articles page 1358
eﬃcacy against dengue virus serotype 2 was low, with the conﬁdence interval crossing zero (35·0% [95% CI –9·2 to 61·0]) in the per-protocol analysis; and 34·7% (10·4–52·3) in the intention-to-treat analysis. However, the estimates for serotype-speciﬁc eﬃcacy are more robust in the present trial than the phase 2b trial because of the larger sample size and various sites at diﬀerent epidemiological settings. Conﬁdence intervals were therefore narrower, and hence previous doubts about the eﬃcacy for serotypes 1, 3, and 4 can be put to rest: eﬃcacy against serotypes 3 and 4 was consistently more than 75% and was 50% for serotype 1. Eﬃcacy against all four serotypes combined will always depend on the serotype distribution at any given time. In this trial, the lower prominence of serotype 2 explains the higher overall eﬃcacy of 56% compared with the Thailand trial, in which the overall eﬃcacy was only 33%. The apparent failure to protect against serotype 2, despite high geometric mean titres after vaccination (as measured by the plaque reduction neutralisation test [PRNT50]) remains an enigma, especially because geometric mean titres are even higher than for the other three serotypes. Are we measuring the wrong antibodies? Or are we measuring the antibodies wrongly? The lessons learnt from the two trials2,3 of this vaccine are that neutralising antibodies measured by the traditional PRNT50 (based on Vero cells) correlate poorly with clinical protection.4 The antibody response in dengue is much more complex than previously thought. Recent ﬁndings suggest that human antibodies neutralise dengue virus infection by binding to a quaternary structure epitope that is expressed only when E proteins are assembled on a virus particle.5,6 In other words, the antibody repertoire might be diﬀerent after natural infection compared with after vaccination. Identiﬁcation of an appropriate immune correlate is now a crucial issue in the development of a dengue vaccine.7 The overall good safety proﬁle in Capeding and colleagues’ trial is consistent with results from previous trials.8 In particular, the absence of more severe disease due to antibody dependent enhancement is reassuring. However, the observation time was only up to 25 months. Experiences from Cuba show that the incidence of severe dengue disease increased as the interval between heterologous infections increased from 4 to 20 years,9 yet another enigma in this complex disease. Longer observation times are needed to 1328
conclusively rule out an increased risk of antibody dependent enhancement in vaccine recipients.10 Indeed, follow-up studies are ongoing in the ﬁve Asian trial sites. Perhaps the most interesting ﬁnding of this trial was that eﬃcacy after at least one dose was almost as high as that after three doses. This ﬁnding is most probably due to an excellent priming eﬀect in a population with high ﬂavivirus exposure (78% in this trial).11 Because three doses 6 months apart is an inconvenient and costly immunisation schedule for scale-up in national programmes, the question of whether suﬃcient eﬃcacy can be achieved with a lower number of doses deserves further assessment. That eﬃcacy in younger age groups was far lower than that in older children (33·7% in children aged 2–5 years vs 74·4% in those aged 12–14 years) is a ﬁnding which is of concern. Yet younger children have a higher incidence of dengue (in most dengue endemic countries including in the cohort of this trial) than older children, and are often at higher risk for more severe disease, although a shift towards older age groups has been reported in most countries in the past decade.1 Of greater concern is the relative lack of vaccine eﬃcacy in participants who were dengue-virus naive (35·5%, 95% CI –26·8 to 66·7), suggesting that this vaccine boosts and broadens pre-existing immunity rather than raising protective immunity, which might also explain the better eﬃcacy in older children exposed to the virus. Therefore, the CYD-TDV vaccine might be of limited use in countries with low dengue endemicity, or in international travellers from non-dengue-endemic countries. However, because of the exploratory nature of the covariate analyses, and the smaller sample size of the baseline serostatus data in the immunogenicity subset, no ﬁrm conclusions can be made. Does an overall eﬃcacy of 56% justify introduction of this dengue vaccine into national immunisation programmes in dengue-endemic countries? With an estimated 96 million clinically apparent dengue infections annually,12 a reduction by half would present a substantial public health beneﬁt that would support vaccine introduction. Furthermore, this trial showed an impressive vaccine eﬃcacy against dengue haemorrhagic fever of 80% (95% CI 52·7–92·4) after one or more injections and 88·5% (58·2–97·9) after three injections; therefore, the main indication for this vaccine should be to protect against severe disease, www.thelancet.com Vol 384 October 11, 2014
reduce hospital admissions and hence health-care costs, and potentially prevent deaths. Even a trivalent vaccine (eg, a vaccine eﬀective only against serotypes 1, 3, and 4) would have a substantial beneﬁt in terms of reducing severe disease,13 which is probably the best news from this trial. Many questions remain to be answered: what is the epidemiological threshold of dengue activity upon which national dengue vaccination programmes are justiﬁed and cost eﬀective given that this vaccine is probably not going to be inexpensive? What about epidemiological settings with a high dominance of serotype 2? Should only high-risk age groups or age groups with the highest vaccine eﬃcacy be targeted? This phase 3 trial may signify the dawn of a new era in dengue control. But the morning fog has not yet lifted as dengue continues to puzzle because of its complex immunology. Whether the armamentarium of alternative vaccine candidates presently in the pipeline (including inactivated, live attenuated, chimeric, recombinant, subunit, and DNA vaccines)14 will improve eﬃcacy beyond 56% remains to be established. For the moment, the CYD-TDV vaccine is the best we have. However, with a 56% eﬃcacy this vaccine will never be a single solution. Continued support for the development of other novel strategies, including drugs, improved case management, insecticides, and new approaches to vector control, is needed before eﬀective dengue control becomes a credible prospect.
I was the principal investigator of the adult cohort in the phase 2 dengue vaccine trial by Sanoﬁ Pasteur at the National University Hospital Singapore from 2008 to 2010. Since 2011, I have been the Scientiﬁc Coordinator of DengueTools (www.denguetools.net), an international consortium funded by the European Commission. 1 2
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Murray NE, Quam MB, Wilder-Smith A. Epidemiology of dengue: past, present and future prospects. Clin Epidemiol 2013; 5: 299–309. Capeding MR, Tran NH, Hadinegoro SRS, et al, and the CYD14 Study Group. Clinical eﬃcacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebocontrolled trial. Lancet 2014; published online July 11. http://dx.doi. org/10.1016/S0140-6736(14)61060-6 X. Sabchareon A, Wallace D, Sirivichayakul C, et al. Protective eﬃcacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 2012; 380: 1559–67. Sirivichayakul C, Sabchareon A, Limkittikul K, Yoksan S. Plaque reduction neutralization antibody test does not accurately predict protection against dengue infection in Ratchaburi cohort, Thailand. Virol J 2014; 11: 48. de Alwis R, Smith SA, Olivarez NP, et al. Identiﬁcation of human neutralizing antibodies that bind to complex epitopes on dengue virions. Proc Natl Acad Sci USA 2012; 109: 7439–44. Teoh EP, Kukkaro P, Teo EW, et al. The structural basis for serotype-speciﬁc neutralization of dengue virus by a human antibody. Sci Transl Med 2012; 4: 139ra83. Halstead SB. Identifying protective dengue vaccines: guide to mastering an empirical process. Vaccine 2013; 31: 4501–07. Leo YS, Wilder-Smith A, Archuleta S, et al. Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2–45 y: phase II randomized controlled trial in Singapore. Hum Vaccin Immunother 2012; 8: 1259–71. Guzman MG, Kouri G, Valdes L, Bravo J, Vazquez S, Halstead SB. Enhanced severity of secondary dengue-2 infections: death rates in 1981 and 1997 Cuban outbreaks. Rev Panam Salud Publica 2002; 11: 223–27. Lam SK, Burke D, Capeding MR, et al. Preparing for introduction of a dengue vaccine: recommendations from the 1st Dengue v2V Asia-Paciﬁc Meeting. Vaccine 2011; 29: 9417–22. Qiao M, Shaw D, Forrat R, Wartel-Tram A, Lang J. Priming eﬀect of dengue and yellow fever vaccination on the immunogenicity, infectivity, and safety of a tetravalent dengue vaccine in humans. Am J Trop Med Hyg 2011; 85: 724–31. Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature 2013; 496: 504–07. Gubler D. 70 years on: progress in dengue vaccine development. Vaccine Companion 2011; 4: 1–3. Wilder-Smith A, Macary P. Dengue: challenges for policy makers and vaccine developers. Curr Infect Dis Rep 2014; 16: 404.
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232; Institute of Public Health, University of Heidelberg, Heidelberg, Germany; and Department of Public Health and Clinical Medicine, University of Umeå, Umeå, Sweden [email protected]
Challenges of achieving and tracking MDG 5 Worldwide, maternal mortality has decreased substantially since 1990.1–3 However, the reduction rate is far lower than that needed to achieve the ﬁfth Millennium Development Goal (MDG 5) of a 75% reduction between 1990 and 2015. In The Lancet, Shams El Arifeen and colleagues4 present a country case study for Bangladesh, which is one of the few countries poised to achieve the www.thelancet.com Vol 384 October 11, 2014
target. The maternal mortality ratio (MMR) decreased from 322 deaths per 100 000 livebirths (95% CI 253–391) in 1998–2001 to 194 deaths per 100 000 livebirths (149–238) in 2007–10, amounting to a 5·6% reduction per annum compared with the global ﬁgure of 2·6%.1 This achievement is remarkable considering that Bangladesh is a low-income country ranking 146 on the Human
See Articles page 1366