Comment
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 head-
to-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
andre.scheen@chu.ulg.ac.be
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.
2 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.
Dengue vaccines: dawning at last?
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
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personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2022. Elsevier Inc. Todos los derechos reservados.
3 Scheen AJ, Radermecker RP. Addition of incretin therapy to metformin in
type 2 diabetes. Lancet 2010; 375: 1410–12.
4 Scheen AJ. GLP-1 receptor agonists or DPP-4 inhibitors: how to guide the
clinician? Ann Endocrinol (Paris) 2013; 74: 515–22.
5 Scheen AJ. Exenatide once weekly in type 2 diabetes. Lancet 2008;
372: 1197–98.
6 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.
7 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.
8 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.
9 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.
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.
11 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.
12 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.
13 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/S0140-
6736(14)60976-4.
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
Science Photo Library
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 Published Online
July 11, 2014
efficacy of 56·5% (43·8–66·4). The overall vaccine efficacy http://dx.doi.org/10.1016/
in the per-protocol analysis was similar to that in the S0140-6736(14)61142-9
intention-to-treat analysis (54·8% [46·8–61·7]). See Articles page 1358
Efficacy was serotype specific. Consistent with the
previous single-centre, phase 2b trial in Thailand,3
1327
 Comment
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
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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.
Annelies Wilder-Smith
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
awilder-smith@ntu.edu.sg
Challenges of achieving and tracking MDG 5
Worldwide, maternal mortality has decreased sub-
stantially 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
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Comment
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 Murray NE, Quam MB, Wilder-Smith A. Epidemiology of dengue: past,
present and future prospects. Clin Epidemiol 2013; 5: 299–309.
2 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, placebo-
controlled trial. Lancet 2014; published online July 11. http://dx.doi.
org/10.1016/S0140-6736(14)61060-6 X.
3 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.
4 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.
5 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.
6 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.
7 Halstead SB. Identifying protective dengue vaccines: guide to mastering an
empirical process. Vaccine 2013; 31: 4501–07.
8 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.
9 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.
10 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.
11 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.
12 Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of
dengue. Nature 2013; 496: 504–07.
13 Gubler D. 70 years on: progress in dengue vaccine development.
Vaccine Companion 2011; 4: 1–3.
14 Wilder-Smith A, Macary P. Dengue: challenges for policy makers and
vaccine developers. Curr Infect Dis Rep 2014; 16: 404.
target. The maternal mortality ratio (MMR) decreased See Articles page 1366
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
1329