Received: 26 October 2023 Revised: 01 December 2023 Accepted: 04 December 2023

DOI: 10.48309/JMPCR.2024.422416.1026

FULL PAPER

The recent development of dengue vaccine: a

review
Rahadian Zainula,b,* |Arif Nur Muhammad Ansoric,d,e,f,g |Ahmad Affan Ali Murtadlod,g,h |Teguh
Hari Suciptoi |Viol Dhea Kharismad,g,h |Muhammad Hermawan Widyanandad,j | Bayyinatul
Muchtaromahk | Amaq Fadholly l,m | Muhammad Khaliim Jati Kusalam | Vikash Jakhmolae
|Maksim Rebezov n ,o | Sukma Sahadewa p |Putu Angga Wiradana q

aDepartment of Chemistry, Faculty of Mathematics and

Dengue fever, caused by the dengue virus, is a
Natural Sciences, Universitas Negeri Padang, Padang,
Indonesia significant global health concern, with millions of
bCenter for Advanced Material Processing, Artificial cases reported annually. The absence of specific
Intelligence, and Biophysic Informatics (CAMPBIOTICS),
Universitas Negeri Padang, Padang, Indonesia
antiviral treatments or effective preventive
cPostgraduate School, Universitas Airlangga, Surabaya, measures has fuelled the urgent need for a
Indonesia dengue vaccine. This provides a comprehensive
dGenerasi Biologi Indonesia Foundation, Gresik, Indonesia
eUttaranchal Institute of Pharmaceutical Sciences,
review of the development of a dengue vaccine,
Uttaranchal University, Dehradun, India summarizing the major milestones, challenges
fEuropean Virus Bioinformatics Center, Jena, Germany
gDivision of Research and Development, Jalan Tengah,
encountered, and recent advancements in this
Pasuruan, Indonesia field. This study explores various vaccine
hDepartment of Biology, Faculty of Science and Technology,
strategies employed, including live attenuated
Universitas Airlangga, Surabaya, Indonesia vaccines, inactivated vaccines, recombinant
iDengue Study Group, Institute of Tropical Disease,
Universitas Airlangga, Surabaya, Indonesia subunit vaccines, and viral vector-based
jDepartment of Biology, Faculty of Mathematics and Natural
vaccines. In addition, the manuscript discusses
Sciences, Universitas Brawijaya, Malang, Indonesia
kMaster Program of Biology, Universitas Islam Negeri the clinical trials conducted to evaluate the
Maulana Malik Ibrahim, Malang, Indonesia safety and efficacy of these vaccine candidates.
lSchool of Veterinary Medicine and Biomedical Sciences, IPB

University, Bogor, Indonesia

mResearch Center for Veterinary Sciences, National Research

and Innovation Agency, Bogor, Indonesia

nDepartment of Scientific Research, Ural State Agrarian

University, Yekaterinburg, Russian Federation

oDepartment of Scientific Research, V. M. Gorbatov Federal

Research Center for Food Systems, Moscow, Russian

Federation
pFaculty of Medicine, Universitas Wijaya Kusuma Surabaya,

Surabaya, Indonesia
qResearch Group of Biological Health, Study Program of

Biology, Faculty of Health and Science, Universitas Dhyana

Pura, Bali, Indonesia

*Corresponding Author:
Rahadian Zainul
KEYWORDS
Tel: +62 812-6138-53
Dengue; dengue virus; medicine; vaccine
morbidity and mortality rates in tropical and
Introduction subtropical regions [1-5]. According to the
World Health Organization (WHO), there are
The history of dengue fever, a vector-borne
approximately 390 million dengue infections
disease caused by the dengue virus and
worldwide each year; this may trigger the
transmitted to human through the bite of
development of a vaccine to prevent the
infected Aedes mosquitoes, is marked by
spread of virus infection [6]. The development
global epidemic outbreaks and substantial

J. Med. Pharm. Chem. Res. 6(2024) 362-382 P a g e | 362

The recent development of dengue … P a g e | 363

of a safe, affordable, and efficacious dengue The development of a dengue vaccine has
vaccine is a public health priority that has been shaped by a range of factors, including
been long overdue. The journey toward scientific and technical challenges, ethical
creating a viable vaccine has been fraught considerations, and market dynamics.
with challenges due to the complexity of Regulatory aspects, such as the approval
dengue virus and the risk of antibody- process and post-marketing surveillance, also
dependent enhancement (ADE) that leads to play a crucial role. It is necessary to
severe dengue [7]. comprehend these intricacies to understand
Dengue virus classification generally the current state of dengue vaccine
consists of four serotypes namely DENV-1, development and what the future may hold
DENV-2, DENV-3, and DENV-4, each capable of [15].
causing the full spectrum of disease severity. As the dengue pandemic continues to
This complexity has posed significant hurdles expand in geographic range and intensity, the
for vaccine development. The ideal dengue quest for an effective vaccine has become even
vaccine should confer protection against all more crucial. It is necessary to understand the
four serotypes simultaneously to prevent past challenges, current advancements, and
ADE. ADE occurs when pre-existing non- future directions in dengue vaccine
neutralizing antibodies from a previous development. This review aims to provide an
infection with one dengue serotype enhance overview of the progress in dengue vaccine
the entry of a different serotype into host development, discussing the different vaccine
cells, increasing viral replication and platforms, the role of regulatory and ethical
potentially leading to severe disease [8,9]. considerations, and prospects for future
The first vaccine for dengue, Dengvaxia vaccines [16,17].
(CYD-TDV) developed by Sanofi Pasteur, was
licensed in 2015. This tetravalent live- Structure of dengue virus
attenuated vaccine is based on a yellow fever The dengue virus belongs to the Flavivirus
17D vaccine backbone and has been genus and has a complex structure consisting
recommended by the WHO for use in certain of three main components: the viral envelope,
endemic regions in individuals aged 9-45 the capsid, and the viral RNA genome.
years with evidence of a prior dengue Understanding the structure of the dengue
infection. However, this vaccine has faced virus is essential for developing effective
challenges, including less than optimal vaccines and antiviral therapies [1-3].
efficacy, particularly against DENV-2, and Dengue virus has an envelope layer
increased risk in previously uninfected composed of glycoprotein (E) and membrane
(seronegative) people possibly developing (M). The E protein plays a crucial role in viral
severe dengue disease [10,11]. entry into host cells and is the main target for
Further efforts to develop a more effective neutralizing antibodies. It is responsible for
and safer vaccine have led to the exploration mediating viral attachment, membrane fusion,
of different vaccine platforms, such as subunit, and host cell receptor recognition [18,19].
DNA, mRNA, viral vector, and inactivated virus The M protein lies beneath the E protein
vaccines. Notably, the Takeda’s TAK-003, a and is involved in the assembly and budding
live-attenuated tetravalent dengue vaccine, of viral particles. It also plays a role in the
has shown promise in Phase III trials with virus's interaction with the host immune
better efficacy and safety profile compared to system. The E and M proteins together form
Dengvaxia. However, long-term data on its the outer shell of the virus, giving it its
protective immunity are still awaited [12-14]. characteristic spherical shape [18,19].
 P a g e | 364 R. Zainul et al

The viral capsid, or core, is located beneath have shown promise in preclinical and early
the viral envelope and encloses the viral RNA clinical studies [24].
genome. The capsid protein (C) is responsible The structural complexity of dengue virus
for maintaining the structural integrity of viral poses challenges in vaccine development. The
particle. It also assists in viral replication and high genetic similarity between serotypes
packaging of the viral RNA during assembly. requires the vaccines development that can
The dengue virus genome is a single-stranded provide simultaneous and balanced protection
positive-sense RNA molecule approximately against all four serotypes. The structural
11 kilobases in length. It serves as the variation between serotypes further
blueprint for viral replication and protein complicates the design of broadly protective
synthesis. The RNA genome is organized into a vaccines [25].
single open reading frame (ORF) flanked by The structure of the dengue virus is a
untranslated regions (UTRs) at the 5' and 3' dynamic and intricate assembly of viral
ends. The ORF encodes three structural proteins and RNA. Understanding the
proteins (C, E, M) and seven nonstructural structural components and their functions is
proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, crucial for the development of effective
and NS5). The non-structural proteins are vaccines and antiviral strategies against
involved in various aspects of viral replication, dengue. Continued research into the
assembly, and immune evasion [18,19]. structural biology of dengue virus will
The dengue virus exists as four distinct contribute to our understanding of the virus-
serotypes, DENV-1, DENV-2, DENV-3, and host interactions and aid in the development
DENV-4, which share approximately 60-75% of interventions to control and prevent
genetic similarity. The serotypes differ in their dengue infections [26].
antigenic properties, allowing for the
possibility of sequential infections with Genome of dengue virus
different serotypes. This phenomenon, known The genome of dengue virus is a single-
as serotype-specific immunity, plays a crucial stranded positive-sense RNA molecule that
role in the development of dengue vaccines serves as the genetic blueprint for viral
[20,21]. replication and protein synthesis.
Structural studies, including X-ray Understanding the structure and organization
crystallography and cryo-electron microscopy, of the dengue virus genome is essential for
have provided valuable insights into the unravelling its replication mechanisms,
three-dimensional structure of dengue virus. genetic diversity, and the development of
These studies have elucidated the effective diagnostic tools and antiviral
arrangement of the viral proteins and their strategies [27].
interactions with host receptors and The dengue virus genome is approximately
antibodies, aiding in the development of 11 kilobases in length and contains a single
antiviral therapies and vaccine candidates open reading frame (ORF) flanked by
[22,23]. untranslated regions (UTRs) at the 5' and 3'
The structural information has also ends. The ORF encodes a polyprotein that is
facilitated the design of recombinant subunit subsequently cleaved into three structural
vaccines that utilize specific domains of the E proteins (C, prM/M, E) and seven
protein to elicit an immune response. EDIII nonstructural proteins (NS1, NS2A, NS2B,
domain on protein E can trigger antibody NS3, NS4A, NS4B, and NS5) (Figure 1). These
production with stronger neutralization proteins play critical roles in viral replication,
properties. Recombinant EDIII-based vaccines assembly, and immune evasion [27].
The recent development of dengue … P a g e | 365

FIGURE 1 The genome of dengue virus

The 5' and 3' UTRs are non-coding regions The non-structural proteins encoded by
that play essential regulatory roles in viral the dengue virus genome are critical for viral
replication and translation. The 5' UTR replication and evasion of the host immune
contains the viral RNA cap structure, which is response. NS3, for example, has protease,
essential for translation initiation. The 3' UTR helicase, and RNA triphosphatase activities
contains conserved sequences important for essential for viral polyprotein processing and
RNA replication and interacts with viral and RNA replication. NS5 possesses RNA-
host proteins during the replication process dependent RNA polymerase activity to drive
[28]. the viral RNA synthesis process [31].
The dengue virus genome exhibits a high The dengue virus genome's genetic
degree of genetic variability, both within and diversity poses challenges for diagnostic and
between the four serotypes (DENV-1, DENV-2, surveillance efforts. The design of molecular
DENV-3, and DENV-4). This genetic diversity diagnostic assays targeting conserved regions
is attributed to the high mutation rate of the is necessary to ensure accurate detection of all
RNA-dependent RNA polymerase and the four serotypes. In addition, genomic
occurrence of recombination events during surveillance allows for monitoring viral
viral replication. These processes contribute evolution, identification of emerging strains,
to the emergence of new viral variants and the and detection of potential vaccine escape
evolution of viral strains with altered mutants [32].
virulence and antigenic properties [29]. The genome of the dengue virus is also a
Genomic studies have identified conserved target for the development of antiviral
RNA secondary structures within the UTRs strategies. Small molecule inhibitors targeting
that play crucial roles in viral replication and viral enzymes, such as NS3 protease and NS5
translation. These structural elements, known polymerase, have shown promise in inhibiting
as cis-acting replication elements (CREs), are viral replication. Moreover, RNA interference
involved in viral RNA synthesis and interact (RNAi) approaches targeting viral RNA have
with viral and host proteins to facilitate demonstrated antiviral activity against
replication and translation processes [30]. dengue virus in experimental settings [33].
P a g e | 366 R. Zainul et al

Advancements in next-generation Serotypes and Variants of Dengue Virus

sequencing technologies have facilitated Dengue virus exists as four distinct
comprehensive genomic studies of dengue serotypes: DENV-1, DENV-2, DENV-3, and
virus isolates from different geographic DENV-4 (Figure 2). Each serotype shares a
regions. These studies have enhanced our high degree of genetic similarity within its
understanding of viral diversity, transmission own serotype but exhibits significant genetic
dynamics, and identification of molecular divergence between serotypes. Understanding
determinants of viral pathogenesis. This the serotypes and variants of dengue virus is
knowledge contributes to the development of crucial for disease surveillance, vaccine
more effective vaccines and antiviral therapies development, and understanding the dengue
[34]. epidemiology [1-3].
The genome of dengue virus is a single- Within each serotype, multiple genetic
stranded positive-sense RNA molecule that variants or genotypes have been identified.
encodes structural and nonstructural proteins These variants are classified based on genetic
essential for viral replication and evasion of differences, particularly within the envelope
the host immune response. The genetic (E) gene, which encodes the major antigenic
diversity of the dengue virus poses challenges determinants. The genetic diversity of dengue
for diagnosis, surveillance, and control efforts. virus is driven by a combination of
However, the development of genomic evolutionary forces, including mutation,
technology has led to a bright idea to study recombination, and selection pressure from
the evolution and pathogenesis of the virus, the host immune response[35].
and facilitate the development of future
strategies against dengue.

FIGURE 2 Four serotypes of dengue virus

The recent development of dengue … P a g e | 367

Genetic variants within each serotype can The identification of variant-specific

exhibit differences in antigenicity, virulence, neutralizing antibodies has opened up new
and epidemic potential. For example, DENV-2 possibilities for the development of serotype-
has been associated with more severe disease specific vaccines. These vaccines could target
outcomes compared to other serotypes, and specific genetic variants or genotypes within a
specific genetic variants within DENV-2 have serotype, providing enhanced protection
been linked to outbreaks of severe dengue against specific strains of dengue virus.
[36]. Similarly, certain DENV-1 genotypes However, the development and
have been associated with increased epidemic implementation of such variant-specific
potential and higher transmission rates [37]. vaccines present logistical and cost
The identification and tracking of dengue considerations [41].
virus serotypes and variants are essential for
disease surveillance. This enables the RNA replication of dengue virus
alterations tracking in circulating strains,
The RNA replication of dengue virus is a
detection of new introductions, and prediction
complex process essential for the production
of potential disease outbreaks. Genomic
of viral progeny and the establishment of
surveillance using next-generation sequencing
infection within host cells. Understanding the
technologies has revolutionized the field by
mechanisms and key players involved in
providing detailed insights into the genetic
dengue virus RNA replication is crucial for the
diversity and dynamics of dengue virus
development of antiviral strategies and
populations [38].
identification of potential drug targets.
The genetic diversity of dengue virus poses
The replication of dengue virus RNA
challenges for vaccine development. A dengue
genome occurs within specialized replication
vaccine must provide protection against all
complexes that are formed within the host cell
four serotypes to be effective. However, the
cytoplasm. These replication complexes are
differences between serotypes and the
comprised of viral non-structural proteins (NS
potential for immune enhancement between
proteins) and host factors. The NS proteins,
serotypes add complexity to vaccine design.
particularly NS3 and NS5, play central roles in
Vaccines must elicit a balanced immune
viral RNA replication[42].
response that provides protection against all
The NS3 protein possesses multiple
serotypes while avoiding immune
enzymatic activities, including protease,
enhancement [39].
helicase, and triphosphatase, which are
Vaccine development efforts have focused
critical for the processing of the viral
on designing tetravalent vaccines that induce
polyprotein and the unwinding of RNA
immune responses against all four dengue
secondary structures. NS5 is a multifunctional
serotypes simultaneously. However, the
protein with RNA-dependent RNA polymerase
differences in antigenicity and genetic
activity responsible for the synthesis of new
diversity between serotypes make it
viral RNA molecules [43].
challenging to achieve balanced protection.
The RNA replication process is initiated by
Consequently, vaccine candidates may show
the synthesis of a complementary negative-
differential efficacy against different
sense RNA strand, which serves as the
serotypes, which highlights the need for
template for the production of positive-sense
careful evaluation and selection of vaccine
RNA genomes. This step is catalysed by the
candidates based on their immunogenicity
NS5 RNA-dependent RNA polymerase activity.
profiles [40].
The negative-sense RNA strand is synthesized
P a g e | 368 R. Zainul et al

using the positive-sense RNA genome as the factors may offer potential antiviral strategies
template [44]. against dengue [49].
The replication of dengue virus RNA is
guided by conserved RNA structures within Genetic diversity of dengue virus
the 5' and 3' untranslated regions (UTRs) of
Dengue virus exhibits a high degree of genetic
the viral genome. These structures, known as
diversity, both within and between the four
cis-acting replication elements (CREs),
serotypes (DENV-1, DENV-2, DENV-3, and
interact with viral and host proteins to
DENV-4). This genetic diversity has significant
facilitate the initiation and progression of RNA
implications for the epidemiology,
replication. The UTRs also contain signals for
pathogenesis, and vaccine development of
RNA synthesis initiation and termination [45].
dengue. Understanding the dengue virus's
Host factors are crucial for dengue virus
genomic diversity is crucial for effective
RNA replication. Various host proteins are
disease surveillance, prevention, and control
recruited to the viral replication complexes,
strategies. Genetic diversity within each
including those involved in RNA metabolism,
serotype is driven by various evolutionary
translation, and membrane rearrangements.
processes, including mutation, recombination,
The interactions between viral and host
and selection pressure. These processes
proteins modulate the efficiency and fidelity
contribute to the emergence of different
of viral RNA replication [46].
lineages or genotypes within a serotype.
The process of dengue virus RNA
Genetic diversity can result in differences in
replication occurs in close association with
viral fitness, disease severity, and epidemic
endoplasmic reticulum (ER)-derived
potential [50].
membrane components. These membrane
The envelope (E) gene, which encodes the
rearrangements provide a platform for the
major antigenic determinants of the virus,
assembly of viral replication complexes and
exhibits considerable genetic variability. This
protect the viral RNA from host immune
variability contributes to the ability of dengue
surveillance. The viral NS proteins induce the
virus to escape host immune responses and
formation of ER-derived structures, which
leads to the emergence of new antigenic
serve as replication sites [47].
variants. Changes in the E gene can affect viral
The RNA replication of dengue virus is
infectivity, virulence, and antibody
tightly regulated to ensure the balance
recognition [51].
between viral replication and host immune
Recombination events also play a
response evasion. This includes the
significant role in generating genetic diversity
suppression of host innate immune signalling
within dengue virus. Recombination can occur
pathways and the modulation of host
between different serotypes or within the
translation machinery. NS5 protein has been
same serotype. Recombinant viruses can
shown to inhibit the interferon response and
acquire genetic material from multiple
interfere with host protein synthesis [48].
parental strains, leading to the emergence of
Advancements in molecular virology
novel variants with altered phenotypes.
techniques, such as RNA interference (RNAi),
Recombination events can affect viral fitness,
have facilitated the identification of host
disease severity, and transmissibility [52].
factors involved in dengue virus RNA
Dengue virus genetic variation has significant
replication. Genome-wide siRNA screens have
effects on the dynamics of illness transmission
revealed host proteins that are essential for
and epidemiology. Different viral lineages or
viral replication, and targeting these host
genotypes may exhibit variations in
geographic distribution and temporal
The recent development of dengue … P a g e | 369

patterns. Understanding the spatial and emergence of new variants that may impact
temporal distribution of dengue virus variants vaccine effectiveness or diagnostic accuracy.
can help identify high-risk areas, track the Comprehensive genomic surveillance can
spread of outbreaks, and guide public health guide vaccine strain selection, identify vaccine
interventions [53]. escape mutants, and inform public health
Furthermore, genetic diversity impacts the strategies for dengue control [58].
development of dengue vaccines. A successful
dengue vaccine needs to provide protection Dengue virus in Indonesia
against all four serotypes. However, the
Dengue fever is a significant public health
genetic diversity within each serotype poses
concern in Indonesia, with the country
challenges in achieving broad and balanced
experiencing a high burden of dengue virus
protection. Vaccines must elicit immune
transmission. Indonesia is endemic to dengue,
responses that are effective against the
and the incidence of dengue fever remains a
diverse array of strains within each serotype
persistent challenge. Given the presence of all
[54].
four dengue virus strains, the country faces a
The genetic diversity of dengue virus also
complex epidemiological landscape [59].
affects the accuracy of diagnostic assays.
The prevalence of dengue fever in
Molecular-based diagnostic tests, such as
Indonesia is influenced by several factors,
polymerase chain reaction (PCR) assays, rely
including environmental conditions,
on the detection of conserved regions within
population density, and socioeconomic
the viral genome. However, the genetic
factors. The Aedes aegypti mosquito, the
variability of dengue virus can lead to
primary vector for dengue transmission,
mismatches between primers/probes and
thrives in urban and peri-urban areas, leading
circulating strains, impacting the sensitivity
to a higher risk of transmission in densely
and specificity of diagnostic tests [55].
populated regions. The incidence of dengue in
Next-generation sequencing technologies
Indonesia fluctuates throughout the year, with
have revolutionized the study of dengue virus
peaks during the rainy season when mosquito
genetic diversity. These techniques allow for
breeding sites increase [60].
high-throughput sequencing of viral genomes,
Dengue fever poses a substantial burden
providing comprehensive information on the
on the Indonesian healthcare system. The
genetic makeup of viral populations. Genomic
number of reported cases has been steadily
studies have revealed the co-circulation of
increasing over the years, with periodic
multiple lineages and the presence of viral
outbreaks occurring in different regions.
subpopulations within a given serotype [56].
Severe forms of the disease, such as dengue
Phylogenetic analyses of dengue virus
haemorrhagic fever (DHF) and dengue shock
sequences have facilitated the classification of
syndrome (DSS), contribute to significant
strains into distinct lineages and the tracking
morbidity and mortality, particularly among
of viral evolution. These analyses have helped
children [61].
identify the origins of emerging strains,
Several risk factors contribute to the
elucidate transmission patterns, and provide
increased transmission of dengue virus in
insights into the genetic determinants of viral
Indonesia. Rapid urbanization and inadequate
fitness and virulence [57].
waste management create conducive breeding
The genetic diversity of dengue virus poses
sites for Aedes mosquitoes. Climate
challenges for vaccine efficacy and
variability, including temperature and rainfall
surveillance efforts. Continuous monitoring of
patterns, can influence the abundance of
viral strains is essential to detect the
mosquito populations. Socioeconomic factors,
P a g e | 370 R. Zainul et al

such as housing conditions and access to are crucial for guiding evidence-based
healthcare, also impact the risk of dengue interventions [66].
infection [62]. Addressing the dengue virus burden in
Efforts to control dengue virus Indonesia requires a comprehensive approach
transmission in Indonesia face various that integrates vector control measures,
challenges. Limited resources for vector public awareness campaigns, and potentially
control programs, inadequate infrastructure dengue vaccination programs. Continued
for surveillance and early detection, and low efforts to strengthen surveillance systems,
awareness of preventive measures among the enhance healthcare infrastructure, and
population hinder effective control strategies. promote community engagement are crucial
In addition, the complexity of dengue for reducing the impact of dengue fever on the
transmission and diversity of circulating virus Indonesian population. By implementing a
strains pose challenges in vaccine multi-faceted approach and fostering
development and implementation [63]. collaborations, Indonesia can work towards
The Indonesian government has mitigating the burden of dengue and
implemented several strategies to combat improving public health outcomes in the
dengue fever. These include vector control country [67].
measures, such as larval source reduction,
insecticide spraying, and community-based Vaccine Strategies for Dengue
campaigns promoting the use of mosquito
Live-attenuated vaccines
nets and repellents. Health education
programs and public awareness campaigns
Live attenuated vaccines have been a
aim to educate the population about dengue
prominent approach in dengue vaccine
prevention and early recognition of symptoms
development. One such vaccine is Dengvaxia®
[64].
(CYD-TDV), a chimeric tetravalent vaccine
The introduction of dengue vaccination in
developed by Sanofi Pasteur. It incorporates
Indonesia has the potential to contribute
the structural proteins of dengue viruses into
significantly to dengue control efforts.
the yellow fever vaccine backbone. Clinical
However, the implementation of a dengue
trials have shown variable efficacy across
vaccine program requires careful
different populations, with lower effectiveness
consideration of factors such as vaccine
observed in seronegative individuals.
effectiveness, cost-effectiveness, and the
Potential risk of severe dengue virus infection
vaccination integration with existing vector
in seronegative individuals when vaccination
control strategies. Vaccination programs
is associated with this vaccine.
targeting high-risk populations and endemic
Live attenuated vaccines replicate in the
areas can have a significant impact on
host cells but have reduced virulence
reducing dengue burden [65].
compared to wild-type viruses. Upon
Research and collaboration among local
vaccination, the attenuated virus enters host
and international partners are essential for
cells and triggers an immune response. This
advancing dengue control in Indonesia.
immune response includes the production of
Surveillance studies to monitor dengue virus
neutralizing antibodies and the activation of T
circulation, clinical trials to evaluate vaccine
cells, which recognize and target the viral
candidates in local populations, and
antigens. The immune response generated by
operational research to optimize control
the live attenuated vaccine provides
strategies based on local epidemiological data
protection against subsequent dengue virus
infections [68].
The recent development of dengue … P a g e | 371

Inactivated vaccines Recombinant subunit vaccines have shown

variable efficacy in clinical trials. Although
Inactivated vaccines, either using whole-virus they can trigger neutralization activity of
particles or purified antigens, have been antibodies to specific dengue virus serotypes,
explored as an alternative approach. These the coverage level may vary. Enhancing the
vaccines offer potential advantages in terms of immunogenicity and breadth of protection is
safety and standardized production processes. an ongoing challenge for subunit vaccines
However, they have shown limited [72].
immunogenicity and efficacy in clinical trials,
requiring the use of adjuvants or multiple Viral vector-based vaccines
doses to enhance immune responses [69].
Inactivated vaccines elicit an immune Viral vector-based vaccines against dengue
response by presenting the viral antigens to virus are developed by genetically modifying
the immune system. These vaccines primarily non-pathogenic viruses to express dengue
induce the production of neutralizing viral antigens. Commonly used vectors include
antibodies against the viral proteins. The adenoviruses, vesicular stomatitis viruses
immune response may also include the (VSV), alphaviruses, and lentiviruses. The
activation of T cells, contributing to cellular modified viral vectors act as delivery vehicles
immunity. However, compared to live to introduce the dengue viral antigens into
attenuated vaccines, inactivated vaccines host cells [73].
generally induce a weaker cellular immune Viral vector-based vaccines work by
response [70]. infecting host cells with the modified viral
vector, which then produces and presents
Subunit recombination vaccine technology dengue viral antigens to the immune system.
This leads to the activation of both humoral
Development of subunit recombination and cellular immune responses. The immune
vaccine technology against dengue virus response generated by the viral vector-based
through expression of viral proteins or vaccines provides protection against
subunits in recombinant expression systems, subsequent dengue virus infections [73].
such as yeast, bacteria, or mammalian cells. Viral vector-based vaccines induce robust
The selected proteins or subunits are typically immune responses, including the production
those known to induce a strong immune of neutralizing antibodies and the activation
response and offer protection against dengue of cellular immune responses. The
infection [71]. presentation of viral antigens by the viral
Recombinant subunit vaccines induce an vectors enhances the recognition and
immune response by presenting specific viral targeting of the antigens by the immune
antigens to the immune system. These system. These vaccines have demonstrated
antigens often include the envelope (E) and the ability to elicit strong and durable immune
non-structural protein 1 (NS1) of dengue responses against dengue virus [73].
virus. The immune response primarily Each vaccine strategy presents its own
involves the production of neutralizing advantages and challenges in dengue vaccine
antibodies that target the viral antigens and development. Balancing safety,
prevent viral entry into host cells. Some immunogenicity, and efficacy is crucial for the
recombinant subunit vaccines may also successful development of a dengue vaccine.
induce cellular immune responses, although Further research is needed to optimize
to a lesser extent than live attenuated vaccines vaccine formulations, adjuvants, and delivery
[71].
 P a g e | 372 R. Zainul et al

systems to achieve optimal immune responses Individuals with prior exposure to one or
and long-term protection [74]. more dengue serotypes typically exhibit
Furthermore, considerations such as higher immune responses upon vaccination.
vaccine dosing regimens, timing of However, there are conditions where an
vaccination, and age-specific responses need individual who is seronegative to dengue
to be explored to ensure maximum infection may have an increased risk of being
effectiveness. The development of a safe and infected with a different serotype. Careful
effective dengue vaccine that provides long- consideration of serostatus and prior dengue
lasting immunity against all four serotypes exposure is crucial in determining vaccine
remains a significant global health priority safety and efficacy in different target
[74]. populations [77].

Clinical Trials and Regulatory Regulatory considerations

Considerations
Regulatory authorities play a vital role in
Clinical trials for dengue vaccines evaluating the safety and efficacy of dengue
vaccine candidates. Stringent regulatory
Clinical trials play a crucial role in assessing processes ensure that vaccines meet the
the safety, immunogenicity, and efficacy of necessary quality, safety, and efficacy
dengue vaccine candidates. These trials standards before approval for public use.
typically follow a phased approach, starting Regulatory agencies assess clinical trial data,
with Phase 1 studies to evaluate safety and including immunogenicity, efficacy, and safety
dosing in a small group of healthy volunteers. outcomes, to make informed decisions
Phase 2 trials expand the sample size and regarding licensure and recommendations for
assess immunogenicity and dosage vaccine use [78].
optimization. Phase 3 trials involve larger
populations and evaluate vaccine efficacy and Post-licensure surveillance and long-term
safety in endemic areas with diverse dengue safety
serotypes [75].
Post-licensure surveillance is crucial for
Immunogenicity and efficacy endpoints monitoring the long-term safety and
effectiveness of dengue vaccines in real-world
Immunogenicity endpoints in dengue vaccine settings. It allows for the detection of rare
trials often include the measurement of adverse events and provides ongoing data on
neutralizing antibody titers, as well as cell- vaccine performance, including duration of
mediated immune responses. Efficacy protection and waning immunity. Robust
endpoints focus on the prevention of surveillance systems facilitate the early
symptomatic dengue cases or the reduction of detection and management of any potential
severe disease, hospitalizations, and deaths. safety concerns [79].
Vaccine efficacy is determined by comparing
the incidence of dengue in vaccinated and Vaccination strategies and implementation
placebo/control groups over a defined period
[76]. The introduction of a dengue vaccine into
immunization programs requires careful
Serostatus and prior dengue exposure consideration of factors such as target
populations, age groups, and optimal
Prior dengue exposure and serostatus can vaccination strategies. Integrated vector
significantly impact vaccine effectiveness. control measures, public awareness
The recent development of dengue … P a g e | 373

campaigns, and sustainable vaccine delivery time of vaccination. There is an ongoing

systems are essential components of debate over what constitutes a robust
successful dengue control programs. measure of vaccine efficacy [86].
Comprehensive understanding of the clinical Further challenges include the logistical and
trial process, regulatory considerations, and economic factors of vaccine distribution and
post-licensure surveillance is critical for the administration, particularly in resource-
successful development, evaluation, and limited settings. Vaccine implementation
implementation of dengue vaccines. strategies need to account for the cost-
Continued collaboration between researchers, effectiveness, accessibility, and the cold chain
regulatory agencies, and public health infrastructure for vaccine storage and
authorities is key to advancing dengue vaccine transportation. Vaccination campaigns also
development and ultimately reducing the need to ensure high coverage to achieve herd
global burden of dengue fever [80]. immunity [87].
On the regulatory front, ensuring the
Challenges and Future Perspectives ethical conduct of clinical trials, particularly in
resource-limited, dengue-endemic countries,
One of the main challenges in dengue vaccine
poses a significant challenge. Vaccine trials
development is the complexity of the dengue
should adhere to the highest ethical
virus itself. Infection with one of the four
standards, which include informed consent,
dengue virus serotypes, DENV-1, DENV-2,
ensuring a favourable risk-benefit ratio for
DENV-3, and DENV-4, does not confer long-
participants, and post-trial access to the
term immunity or against infection with other
vaccine [88].
serotypes. This increases the risk of severe
Looking forward, newer vaccine platforms
dengue during subsequent infections, a
such as mRNA and viral vector-based vaccines
phenomenon known as antibody-dependent
offer new possibilities for dengue vaccine
enhancement (ADE). ADE complicates vaccine
development. The success of mRNA vaccines
development as vaccines must be tetravalent,
for COVID-19 provides an optimistic outlook
providing balanced and lasting immunity
for this technology, which offers advantages in
against all four serotypes simultaneously [81-
terms of safety, speed of manufacturing, and
83].
flexibility in changing the encoded antigen
Secondly, the variability of immune
[89,90].
response among individuals, influenced by
Innovative trial designs and statistical
factors such as age, previous exposure to the
methods could also help overcome some of
virus, and co-infections, further complicates
the challenges in evaluating vaccine efficacy.
the development and evaluation of a dengue
Composite endpoints, long-term follow-up to
vaccine. This was highlighted by the issue
evaluate duration of protection, and multi-
with Dengvaxia, where it was found to
regional trial designs could provide more
increase the risk of severe dengue in those
robust measures of efficacy [91-93].
who had not been previously exposed to the
There is also a need for more detailed
virus (seronegative individuals) [84,85].
understanding of the immune response to
The interpretation of clinical trial results
dengue infection and vaccination, including
presents another challenge. The endpoints
the mechanisms behind ADE. This could help
used to evaluate vaccine efficacy in clinical
in the development of new vaccine candidates
trials can be influenced by a multitude of
and immunization strategies, and in
factors, including the level of dengue virus
predicting vaccine performance [92,94].
transmission in the community, the age of the
participants, and their immune status at the
P a g e | 374 R. Zainul et al

Public-private partnerships could play a https://www.orcid.org/0000-0001-9060-0429

pivotal role in overcoming the logistical and Muhammad Hermawan Widyananda
economic challenges of vaccine https://www.orcid.org/0000-0002-0064-8865
implementation. Governments, international Bayyinatul Muchtaromah
organizations, vaccine manufacturers, and https://www.orcid.org/0000-0001-9968-8295
NGOs need to collaborate to ensure the Amaq Fadholly
accessibility and affordability of dengue https://www.orcid.org/0000-0003-2064-8552
vaccines, particularly in resource-limited Muhammad Khaliim Jati Kusala
settings[95,96]. https://www.orcid.org/0000-0002-7613-721X
Vikash Jakhmola
Conclusion https://www.orcid.org/0000-0002-8108-006x
Maksim Rebezov
The development of a safe, effective, and
https://www.orcid.org/0000-0003-0857-5143
affordable dengue vaccine is crucial for
Sukma Sahadewa
combating dengue fever. Advancements in
https://www.orcid.org/0009-0009-9253-7633
dengue immunology have led to various
Putu Angga Wiradana
vaccine strategies, including live attenuated,
https://www.orcid.org/0000-0002-0139-8781
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