Dengue vaccine

From Wikipedia, the free encyclopedia

Dengue vaccine

Vaccine description

Target disease Dengue fever

Type ?

Identifiers

ChemSpider  none

Dengue vaccine is a vaccine to prevent dengue fever in humans. The World Health
Organization only recommends the vaccine as a possible option in areas of the world where the
disease is common.[1] In 2017 the manufacturer recommended that the vaccine only be used in
people who have previously had a dengue infection, as outcomes may be worsened in those who
have not been previously infected.[2] This has caused a scandal in the Philippines where more than
733,000 children were vaccinated regardless of serostatus.[3]
The development of vaccine for dengue fever began as early as 1929, but has been hindered first by
incomplete knowledge of the disease pathogenesis, and later by the need to simultaneously create a
stable immunity against all four dengue serotypes. Several vaccine candidates are in development
including live attenuated, inactivated, DNA and subunit vaccines. Live attenuated vaccine candidates
are the furthest along in development.[4]
In 2016 a partially effective vaccine for dengue fever (Dengvaxia) became commercially available in
11 countries: Mexico, the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay,
Guatemala, Peru, Thailand, and Singapore.[5][6][7] In Indonesia it costs about US$207 for the
recommended three doses.[7] WHO recommends that use be limited to areas where the disease is
common because vaccination may actually increase the risk of dengue fever in people who have not
been previously infected with the dengue virus because of the phenonmenon of antibody-dependent
enhancement.[8]

Contents
[hide]

 1CYD-TDV
 2In development
o 2.1DENVax or TAK-003
o 2.2TetraVax-DV
o 2.3TDENV PIV
o 2.4V180
o 2.5DNA vaccines
o 2.6Manufacturer in India and Vietnam
 3References
 4External links

CYD-TDV[edit]
CYD-TDV, sold under the brand name Dengvaxia and made by Sanofi Pasteur, is a
live attenuated tetravalent chimeric vaccine made using recombinant DNA technology by replacing
the PrM (pre-membrane) and E (envelope) structural genes of the yellow fever attenuated 17D strain
vaccine with those from four of the five dengue serotypes.[9][10] In 2017 the manufacturer
recommended that the vaccine only be used in people who have previously had a dengue infection
as otherwise there was evidence it may worsen subsequent infections.[2] The initial protocol did not
require baseline blood samples prior to vaccination in order to establish an understanding of
increased risk of severe dengue in participants who had not been previously exposed. In November
2017 Sanofi acknowledged that some participants were put at risk of severe dengue if they had no
prior exposure to the infection; subsequently the Philippines government suspended the mass
immunization program with the backing of the WHO which began a review of the safety data.[11]
Ongoing phase III trials in Latin America and Asia involve over 31,000 children between the ages of
2 and 14 years. In the first reports from the trials, vaccine efficacy was 56.5% in the Asian study and
64.7% in the Latin American study in patients who received at least one injection of the
vaccine.[12][13] Efficacy varied by serotype. In both trials vaccine reduced by about 80% the number of
severe dengue cases.[14] An analysis of both the Latin American and Asian studies at the 3rd year of
follow-up showed that the efficacy of the vaccine was 65.6% in preventing hospitalization in children
older than 9 years of age, but considerably greater (81.9%) for children who were seropositive
(indicating previous dengue infection) at baseline.[15] The vaccination series consists of three
injections at 0, 6 and 12 months.[10] The vaccine was approved in Mexico, Philippines, and Brazil in
December 2015, and in El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Indonesia, Thailand
and Singapore in 2016.[5] Tradenamed Dengvaxia, it is approved for use for those aged nine and
older and can prevent all four serotypes.[16]

In development[edit]
DENVax or TAK-003[edit]
DENVax or TAK-003 is a recombinant chimeric vaccine with DENV1, DENV3, and DENV4
components on a dengue virus type 2 (DENV2) backbone originally developed at Mahidol
University in Bangkok and now funded by Inviragen (DENVax) and Takeda (TAK-003).[17][18] Phase I
and II trials are ongoing in the United States, Colombia, Puerto
Rico, Singaporeand Thailand.[19] Based on the latest 18-month data published in the journalLancet
Infectious Diseases, indicated that DENVax/TAK-003 produced sustained antibody responses
against all four virus strains, regardless of previous dengue exposure and dosing schedule.[20]
TetraVax-DV[edit]
TetraVax-DV is a tetravalent admixture of monovalent vaccines that were tested separately for
safety and immunogenicity. The vaccine passed phase I trials and is being tested in phase II studies
in Thailand and Brazil.[21] In Brazil, the studies are being done in collaboration with the Instituto
Butantan.
TDENV PIV[edit]
TDEN PIV is inactivated tetravalent vaccine undergoing phase I trials as part of a collaboration
between GSK and the Walter Reed Army Institute of Research. A synergistic formulation with
another live attenuated candidate vaccine (prime-boost strategy) is also being evaluated in a phase
II study. In prime-boosting, one type of vaccine is followed by a boost with another type in an attempt
to improve immunogenicity.[22]
V180[edit]
Merck is studying recombinant subunit vaccines expressed in Drosophila cells. Studies are in phase
I stage as of 2015.[22]
DNA vaccines[edit]
The Naval Medical Research Center attempted to develop a monovalent DNA plasmid vaccine, but
early results showed it to be only moderately immunogenic.[19]
Manufacturer in India and Vietnam[edit]
Panacea Biotec and Biological E. Limited have vaccine candidates in the earliest stages of
development. A company in Vietnam (VABIOTECH) is conducting safety tests and developing a
clinical trial plan.[23] All three companies are involved in studies of a TetraVax-DV vaccine in
conjunction with the National Institutes of Health.[24]

The dengue vaccine dilemma

The Lancet Infectious Diseases
Published: February 2018

PlumX Metrics
 DOI: https://doi.org/10.1016/S1473-3099(18)30023-9
|
Article Info
 Summary
 Full Text
 Tables and Figures
Dengue is the most common mosquito-transmitted viral infectious disease. A 2016 study
estimated nearly 60 million symptomatic dengue cases worldwide every year (estimates
including asymptomatic cases are at least six times higher), resulting in about 10 000
deaths. 4 billion people are at-risk in 128 countries where aedes mosquito vectors are
present. Efforts to develop a vaccine against dengue have been ongoing for decades. The
first such vaccine to be used routinely is CYD-TDV (marketed as Dengvaxia), a live,
attenuated tetravalent product developed by Sanofi Pasteur. Following two phase 3 clinical
trials published in 2014, Dengvaxia was licenced in December, 2015, and approved in 19
countries. Subsequently, regional mass vaccination programmes were launched in the
Philippines and Brazil, targeting 1 million people. However, after reassessment of data from
the clinical trials, Sanofi warned on Nov 29, 2017, that the vaccine can increase the risk of
severe dengue in particular circumstances. The vaccination programme in the Philippines
has been suspended, with information released to WHO by Sanofi raising questions about
future use of Dengvaxia.

How any vaccine against dengue is used is complicated by the fact that virus occurs in four
serotypes, and immunity against any one serotype does not generate lasting immunity
against the other three, hence the need for a tetravalent vaccine. Furthermore, being
infected with—and developing immunity to—one viral serotype seems to be the trigger that
can lead to a patient having more severe disease manifestations when subsequently
infected with a different serotype, a phenomenon known as antibody-dependent
enhancement. Infections with the third and fourth serotypes, if they occur, usually result in
milder disease.

Expert opinion and a position paper on Dengvaxia were issued by WHO in 2016. When
licenced, the vaccine was approved for people aged 9–45 years, in which group the phase
3 trials at 2 years of follow-up showed a reduction in severe dengue of 93% and of hospital
admissions due to dengue of 82%. The vaccine was not approved in younger children
because of less favourable efficacy and safety; in particular, an increase in hospital
admissions due to dengue among those aged 2–5 years. This finding, which might have
been an effect of age or because of more dengue-unexposed (ie, seronegative) individuals
in the younger age group, could not then be explained since serostatus before immunisation
was unknown for most trial participants. However, some experts warned in 2016 that the
increased risk of hospital admission was a serious safety concern, including Maíra Aguiar
and colleagues in this journal, a point emphasised by Aguiar and Nico Stollenwerk in their
Correspondence published online on Dec 21, 2017.

Sanofi's statement in November came about because—prompted by WHO—the company

developed an assay to estimate dengue serostatus before vaccination in trial participants. A
supplemental statement from WHO on Dec 22, 2017, verifies that overall Dengvaxia
 reduces the risk of confirmed severe dengue and hospital admissions. Vaccine recipients
presumed to be seropositive at immunisation had sustained protection during 5 years'
follow-up. However, among recipients seronegative before immunisation—and regardless of
age at vaccination—there was a higher risk of severe dengue disease and hospital
admission compared with unvaccinated controls. Thus, in seronegative individuals, the
vaccine seems to enhance the severity of subsequent dengue infection.

Where then do these findings leave the status of Dengvaxia and other candidate vaccines
against dengue? The Dec 22 WHO statement notes that in settings of high dengue
seroprevalence, the vaccine is likely still beneficial at a population level. However, Aguiar
and Stollenwerk state that “ethically no one should have been put under risk by receiving
this vaccine”. Age was clearly used as a proxy for seropositive status in the original
recommendations, a position that is no longer tenable. Indeed, the new WHO
recommendation is for vaccination only in individuals with proven past dengue infection. But
no point-of-care test for dengue serostatus exists. In a phase 2 trial of the Takeda TDV
tetravalent dengue vaccine published in this issue, serostatus at the time of vaccination was
measured, but follow-up is too short to detect risks associated with being seronegative.
Phase 3 trials of the Takeda vaccine and another from the Instituto Butantan, Brazil, whose
primary completion dates are later this year, might provide more answers. A new position
paper from WHO is also expected later this year. In the meantime, a rapid assay of dengue
serostatus is surely a priority.

Dengue Vaccine: The Need, the Challenges,

and Progress
Alan L. Rothman Francis A. Ennis

The Journal of Infectious Diseases, Volume 214, Issue 6, 15 September 2016, Pages 825–
827, https://doi.org/10.1093/infdis/jiw068
Published:

16 February 2016

Article history

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(See the brief report by Durbin et al on pages 832–5.)

With regard to scientific progress on dengue, it could be said that we are living in the best of
times and the worst of times. As recently as the 1980s, dengue was considered among the so-
called neglected tropical diseases. Initiatives through organizations such as the National
Institutes of Health, the World Health Organization, and the Bill and Melinda Gates Foundation
greatly increased the visibility of dengue and the financing of basic and translational research.
These initiatives, along with advances in scientific technology, have led to an explosion of
knowledge and remarkable progress in the development of novel approaches to prevention,
diagnosis, and treatment of dengue. Within just the past 5 years, the first dengue vaccine entered
phase 3 clinical trials; demonstrated efficacy against both the primary end point of virologically
confirmed dengue and important secondary end points, including cases of hospitalized dengue
and dengue hemorrhagic fever; and reached licensure in several dengue-endemic countries. The
challenges overcome in reaching these milestones should not be understated [1]. In addition to
the complexity of developing a vaccine against all 4 dengue virus (DENV) serotypes, the
potential to induce harmful immune responses has been a major impediment to translating the
basic vaccine concept into a vaccine formulation ready for advanced clinical testing. Protective
immunity induced by natural DENV infection is predominantly serotype specific after the first
few months. However, individuals with such protective immunity have an increased risk for
more-severe forms of dengue—dengue hemorrhagic fever and dengue shock syndrome—during
a second DENV infection with a heterologous DENV serotype, compared with individuals who
have never had DENV infection. The increased risk for severe disease appears to be most
strongly associated with the second DENV infection, and it is clear that broadly protective
immunity can eventually be generated. It was uncertain whether, without a period of increased
risk, such protective immunity could be induced by a vaccine. The lack of reliable
immunological markers distinguishing fully protected individuals from those at elevated risk,
along with the absence of faithful animal models of this phenomenon, have required something
of a leap of faith on the part of vaccine developers, investigators, and participants. With a tool
now in hand with the potential to reduce the risk of dengue, particularly its more-severe forms,
we have some cause to celebrate.
The magnitude and urgency of the need for an effective dengue vaccine temper any celebration,
however. DENV and its Aedes mosquito vectors have proven not only highly resilient but
extraordinarily well suited to exploit human economic development. The past few decades have
seen an expansion of areas where dengue is considered endemic, with half the human population
now at risk of infection [2]. The average number of dengue cases reported annually has increased
alarmingly in each of the past 4 decades. Healthcare systems are overloaded on a regular basis by
the case load, especially in resource-limited countries, but even highly developed countries,
including the United States, Japan, and Singapore, have proved to be susceptible to chains of
local transmission. Despite the much enhanced profile for dengue among researchers, funding
agencies, pharmaceutical and vaccine companies, and the lay public, we have clearly been losing
the battle against the virus and the mosquito.

Against this backdrop, the Sanofi vaccine that was recently licensed, a tetravalent live attenuated
vaccine formulation comprising chimeric flaviviruses containing the structural protein genes of
DENV and the nonstructural protein genes of the yellow fever virus 17D vaccine strain, while an
important step, leaves much to be desired. The approved regimen involves 3 doses given at 6-
month intervals, a logistical challenge, particularly in resource-poor countries. Efficacy against
serotype 2 viruses was, at best, suboptimal. More concerning, efficacy against the primary end
point was significantly lower in children 2–5 years of age and subjects who were seronegative
for DENV at baseline (ie, individuals with no previous DENV infections); during the first year of
long-term safety monitoring (the second year after completion of the vaccination series), there
was even a statistically significant increase in hospitalized dengue cases among children in the
youngest age stratum who received the vaccine [3]. As a result, the vaccine has been licensed
only for use in children ≥9 years of age, missing an important segment of the population at risk.
While no adverse safety signals were observed in the vaccine trials among this older age group,
follow up has been relatively short, and there are remaining concerns about the durability of
vaccine-induced protective immunity and the potential for enhanced risk if protective immunity
wanes over time.

The weaknesses in the Sanofi dengue vaccine create both the need and the opportunity for other
dengue vaccine candidates. One of the candidates in advanced clinical development is the
product of >20 years of intramural research at the National Institutes of Allergy and Infectious
Diseases that involved the production and testing of dozens of candidate DENV vaccine strains
attenuated by targeted mutation and/or chimerization [4]. Through extensive preclinical and
phase 1 clinical testing, these dozens of strains were winnowed down to a single representative
of each DENV serotype with favorable safety and immunogenicity profiles. A tetravalent live
attenuated vaccine formulation referred to as TV003 has recently entered phase 3 clinical testing.
Studies to date show an acceptable safety profile, notable for the frequent occurrence of very
minor rashes, and an encouraging neutralizing antibody response profile after a single
immunization. But will this vaccine be protective, and, if so, will protective immunity be
durable?

In the current issue of The Journal of Infectious Diseases, Durbin et al provide a further piece of
evidence to support the potential efficacy of TV003 [5]. The authors provide a brief summary of
the neutralizing antibody responses detected 1 year after a first dose and then after a second dose.
There were no significant adverse effects in this small study, and the results suggest that the
vaccine is immunogenic for 1 year for all 4 DENV serotypes and that a second dose after 1 year
does little to enhance the antibody response to the first dose. In this and other studies, the vaccine
appears to be very attenuated, with low viremia levels detected after dose 1 and no viremia
detected after dose 2. The authors are performing 5-year efficacy trials to determine whether the
vaccine induces protection. In interpreting their current results, they acknowledge that is it “not
possible to unequivocally equate resistance to revaccination with protection against natural
infection” [5]. Even greater caution is warranted, however. From studies with another live virus
vaccine, we know that antibody levels sufficient to provide protection against a dose of measles
vaccine are inadequate for protection against wild-type measles virus infection by the respiratory
route in infants with persistent maternal antibodies [6]. Thus, levels of antibodies that may
prevent viremia in response to a live attenuated vaccine may not protect against natural virus
infection. Especially with the complexity of 4 DENV serotypes and the known increased risk for
severe dengue during secondary infections, it will be very important to determine whether a
dengue vaccine induces a balanced long-term protection against all 4 serotypes and whether a
booster dose may be needed at some point.

Unlike other viral diseases, such as poliomyelitis [7], yellow fever, or mumps [8], dengue can
occur in the presence of detectable levels of serum neutralizing antibodies [9, 10]. Higher levels
of neutralizing antibodies correlate better with protection than low or undetectable levels of
antibodies. The planned longer-term studies should help to determine whether a balanced
neutralizing antibody response is maintained and identify correlates of protection. In a dengue-
endemic region, exposure to DENV may boost vaccine-induced immune responses, which would
not occur in individuals living in areas that are dengue free.

In summary, dengue is a major and increasing public health burden causing high levels of
morbidity and significant mortality in much of the world. Progress in dengue vaccine
development over the last 50 years has been limited. Recently, a first-generation vaccine has
been developed that induces significant but serotype-variable protection after multiple doses.
Several other candidate vaccines are being developed. The article by Durbin et al shows
convincing, robust antibody responses to all 4 serotypes of DENV after a single dose of a
candidate live attenuated vaccine. These are promising results in the search for a safe and
 effective dengue vaccine for general use in dengue-endemic areas. Long-term safety and efficacy
data will be awaited with interest.

Notes

Financial support. This work was supported by the National Institute of Allergy and
Infectious Diseases (grant P01 AI034533 to A. L. R.).

Potential conflict of interest. A. L. R. has received compensation from Sanofi Pasteur as a

scientific advisory board member for the dengue vaccine program. F. A. E. certifies no potential
conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript
have been disclosed.

Philippines Orders
Probe into Suspended
Dengue Vaccine
Administered to
730,000 Kids
French drug company Sanofi announced that the
inoculation could sometimes worsen the disease
 By Manolo Serapio Jr, Neil Jerome Morales, Reuters on December 4, 2017



Credit: Dondi Tawatao Getty Images
MANILA (Reuters)—The Philippines ordered a probe on Monday into the
immunization of more than 730,000 children with a vaccine for dengue that
has been suspended following an announcement by French drug company
Sanofi (SASY.PA) that it could worsen the disease in some cases.

Amid mounting public concern, Sanofi explained its “new findings” at a news
conference in Manila, but it did not say why action was not taken after a World
Health Organization (WHO) report in mid-2016 that identified the risk it was
now flagging.

A non-governmental organization (NGO) said it had received information that

three children who were vaccinated with Dengvaxia had died and a senator
said he was aware of two cases.
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However, Department of Health Undersecretary Gerardo Bayugo told Reuters
that the three referred to by the NGO died due to causes not related to the
vaccine, and Sanofi said no deaths had been reported as a result of the
program.

“As far as we know, as far as we are made aware, there are no reported deaths
that are related to dengue vaccination,” said Ruby Dizon, medical director at
Sanofi Pasteur Philippines.

Last week, the Philippines Department of Health halted the use of Dengvaxia
after Sanofi said it must be strictly limited due to evidence it can worsen the
disease in people not previously exposed to the infection.

In a statement, Sanofi said the long-term safety evaluation of the vaccines

showed significantly fewer hospitalizations due to dengue in vaccinated people
over 9 years old compared with those who had not been vaccinated.
Nearly 734,000 children aged 9 and over in the Philippines have received one
dose of the vaccine as part of a program that cost 3.5 billion pesos ($69.54
million).
ADVERTISEMENT
The Department of Justice on Monday ordered the National Bureau of
Investigation to look into “the alleged danger to public health ... and if
evidence so warrants, to file appropriate charges thereon.”

There was no indication that Philippines health officials knew of any risks
when they administered the vaccination.

However, the WHO said in a July 2016 research paper that “vaccination may
be ineffective or may theoretically even increase the future risk of hospitalized
or severe dengue illness in those who are seronegative at the time of first
vaccination regardless of age.”

Singapore’s Health Sciences Authority said last week that it flagged risks when
Dengvaxia was approved there in October 2016, and was working with Sanofi
to strengthen risk warnings on the drug’s packaging.

According to Sanofi in Manila, 19 licenses were granted for Dengvaxia, and it

was launched in 11 countries, two of which—the Philippines and Brazil—had
public vaccination programs.
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“A SHAMELESS SCAM”

A spokesman for Philippines President Rodrigo Duterte said on Sunday the

government would hold to account those responsible for the program.

“We will leave no stone unturned in making those responsible for this
shameless public health scam, which puts hundreds of thousands of young
lives at risk, accountable,” spokesman Harry Roque said in a statement.

Former Health Secretary Janette Garin, who implemented the program under
the administration of then-President Benigno Aquino, said she welcomed the
investigation.

“In the event that there will be authorities who will point culpability to me, I
am ready to face the consequences,” she told ANC TV. “We implemented it in
accordance with WHO guidance and recommendations.”

Roque said there had been no reported case of “severe dengue infection” since
the vaccine was administered and urged the public “not to spread information
that may cause undue alarm”.
ADVERTISEMENT
 Volunteers Against Crime and Corruption, an NGO, said it was checking a
report that three children on the northern island of Luzon had died since
being vaccinated in April 2016, but the Department of Health said the deaths
were not due to Dengvaxia.

“When we evaluated the clinical records, it was not related to the dengue
vaccination,” Undersecretary Bayugo said.

A prominent senator, Richard Gordon, told Reuters he was aware of two

deaths—but gave no details—and said approval and procurement for the
program was done with “undue haste”.

Dengue is a mosquito-borne tropical disease. Although it is not as serious as

malaria, it is spreading rapidly in many parts of the world, killing about
20,000 people a year and infecting hundreds of millions.

While Sanofi’s Dengvaxia is the first-ever approved vaccine for dengue,

scientists already recognized it was not perfect and did not protect equally
against the four different types of the virus in clinical tests.
ADVERTISEMENT
A new analysis from six years of clinical data showed that Dengvaxia vaccine
provides persistent protective benefit against dengue fever in those who had
prior infection.

But for those not previously infected by the virus, more cases of severe disease
could occur in the long term following vaccination, Sanofi said.

Sanofi ordered to pull dengue vaccine

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Philippines wants French drugmaker to cover immunisation program costs

Source: Getty images

Sanofi’s Dengvaxia dengue vaccine has been withdrawn in the Philippines, and the
government is demanding a refund from the company of the PHP3.5 billion (£52
million) it had paid for the vaccines as part of an immunisation programme.

The decision comes in the light of an analysis of long-term data on the vaccine, gathered
over six years, which indicated that its performance was dependent on previous
infection with the mosquito-borne dengue virus. The analysis showed that the vaccine
gives persistent protective benefit against dengue in those who had previously been
infected with the virus. However, there were more cases of severe disease if the first
infection occurred after vaccination.

‘These findings highlight the complex nature of dengue infection,’ says Su-Peing Ng,
Sanofi Pasteur’s global medical head. ‘We are working with health authorities to ensure
that prescribers, vaccinators and patients are fully informed of the new findings, with
the goal of enhancing the impact of Dengvaxia in dengue-endemic countries.’

The company was criticised by a joint hearing of the government’s public accountability
and health & good government committees, according to a report in The Philippine
Daily Inquirer. Sanofi Pasteur Asia Pacific head Thomas Triomphe maintained that the
advisory about the vaccine was not a cause for panic and alarm, and it remained safe.
However, the committee was unhappy.

‘We need to do something … because of your statement,’ said representative Estrelita

Suiansing. ‘It is Sanofi itself who issued the advisory that there is a problem.’

Triomphe was forced to apologise, the newspaper reports. ‘I want to provide the facts
and I want people to understand there’s no need to panic,’ he said. ‘I do apologise if
there’s a misunderstanding.’
 Sanofi is now looking to update the prescribing information to request that healthcare
professionals assess the likelihood of previous infection before vaccination. Those who
are unlikely to have been infected should not be vaccinated.

There are currently four different serotypes of dengue virus in circulation, and thus
people can be infected up to four times in their lifetime. Data from countries where the
virus is endemic indicate that 70–90% of the population will be exposed to the virus at
least once by the time they reach adolescence. Severe disease is more likely to occur in
people who have already been infected with one serotype when infected by a different
one.

Dengvaxia is a tetravalent live, attenuated vaccine designed to protect against all four
serotypes. It is currently indicated in most dengue-endemic countries. Trials in 10
endemic countries in Asia and Latin America showed it prevented 93% of severe disease
and 80% of hospitalisations.

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Dengue vaccine research
Dengue is a mosquito-borne flavivirus disease that has spread to most tropical and many subtropical areas. The
disease is caused by four closely related viruses, the Dengue viruses 1-4. There are no specific dengue
therapeutics and prevention is currently limited to vector control measures. A dengue vaccine would therefore
represent a major advance in the control of the disease.
Status of vaccine development
The first dengue vaccine, Dengvaxia (CYD-TDV) by Sanofi Pasteur, was first registered in Mexico in
December, 2015. CYD-TDV is a live recombinant tetravalent dengue vaccine that has been evaluated as a 3-
dose series on a 0/6/12 month schedule in Phase III clinical studies. It has been registered for use in individuals
9-45 years of age living in endemic areas.
 Questions and answers on CYD dengue vaccine
 Updated Questions and Answers related to information presented in the Sanofi Pasteur press release on 30
November 2017 with regards to the dengue vaccine Dengvaxia®
WHO recommends that countries should consider introduction of the dengue vaccine CYD-TDV only in
geographic settings (national or subnational) where epidemiological data indicate a high burden of disease.
Complete recommendations may be found in the WHO position paper on dengue.
 WHO position paper on dengue
pdf, 437kb
 Tools to support decision-making for the addition of the licensed dengue vaccine into a public immunization
programme
There are approximately five additional vaccine candidates under evaluation in clinical trials, including other
live-attenuated vaccines, as well as subunit, DNA and purified inactivated vaccine candidates. Additional
 technological approaches, such as virus-vectored and VLP-based vaccines, are under evaluation in preclinical
studies.
The growing global epidemic of dengue is of mounting concern, and a safe and effective vaccine is urgently
needed. WHO expects vaccines to be an integrated part of the Global dengue prevention and control strategy
(2012-2020).
 WHO report: global strategy for dengue prevention and control, 2012–2020
Advisory groups
 SAGE Working Group on Dengue Vaccines and Vaccination
Challenges to vaccine development
Infection by one of the four dengue virus serotypes has been shown to confer lasting protection against
homotypic re-infection, but only transient protection against a secondary heterotypic infection. Moreover,
secondary heterotypic infection is associated with an increased risk of severe disease. This and other
observations suggest an immunopathological component in dengue pathogenesis, which is referred to as immune
enhancement of disease. Due to these dengue-specific complexities, vaccine development focuses on the
generation of a tetravalent vaccine aimed at providing long-term protection against all virus serotypes.
Additional challenges are posed by the lack of an adequate animal disease model and the resulting uncertainty
around correlates of protection. In spite of these challenges, vaccine development has made remarkable progress
in recent years, and the current dengue vaccine pipeline is advanced, diverse and overall promising.
WHO activities
The WHO Initiative for Vaccine Research (IVR), in collaboration with a wide range of partners, aims to
facilitate the development and future introduction of safe, effective and affordable dengue vaccines. Activities
focus on the following main objectives:
 Identify knowledge gaps and research needs related to the development, evaluation and implementation of
dengue vaccines.
 Build scientific consensus and develop guidance on the evaluation of dengue vaccines.
 Review and evaluate the evidence base for policy recommendations related to the introduction and use of dengue
vaccines.
 Develop guidance on vaccine implementation, including introduction strategies.
 Support national regulatory authorities in their review of dengue vaccine registration files