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1. Dengue Vaccine, does it Really Matter?
Sri Rezeki S Hadinegoro
UKK Infeksi & Pediatri Tropis, Ikatan Dokter Anak Indonesia
ASMPID 2022, Semarang 16-17 Juli 2022

2. Outline
• Introduction
o Dengue remain a problem in Indonesia
o Ongoing dengue control
• What are the aim for dengue?
• Will vaccines help?
o Vaccines development
o Vaccine safety
o Vaccine efficacy
• Take home message

3. Apa kata Media tentang Dengue?
https://health.detik.com/berita-detikhealth/d-6131955/warning-kasus-
dbd-ri-sepanjang-2022-tembus-45-ribu-kematian-432-jiwa
Provinsi dengan kasus
Dengue tinggi
• Bali
• Kalimantan Utara
• Bangka Belitung
• Kalimantan Timur
• Nusa Tenggara Timur
• DKI Jakarta
• Jawa Barat
• Sulawesi Utara
• Nusa Tenggara Barat
• DI Yogyakarta.

4. “Dengue Burden” pada Anak
• Menurut penelitian seroprevalens dengue pada anak-
anak dan remaja berusia 1-18 tahun
– Seroprevalensi nasional = 69,4%1
– Median usia serokonversi = 4,8 tahun1
– 14% anak-anak dan remaja naif demam berdarah
terinfeksi DENV per tahun2
• Seroprevalensi dengue pada anak tinggi di 34
kabupaten (12 provinsi) di Indonesia3
• Dalam rentang usia 7 bulan hingga <19 tahun
— Estimasi FOI† konstan: 14,7% (12,8–16,9)3
— Usia rata-rata saat serokonversi: 4,7 (4,5–4,9) tahun3‡
— Usia serokonversi 80%: 11 (10,5-11,5) tahun3‡
Rerata seroprevalensi dengue
berdasarkan kelompok usia (N=3198)1*
Seroprevalensi
dengue
(%)
Umur (tahun)
References
• Prayitno, dkk. PLoS Negl Trop Dis 2017;11:e0005621
• Tam, dkk. PLoS Negl Trop Dis 2018;12:e0006932
• Nealon, dkk. J Infect Dis 2020; doi: 10.1093/infdis/jiaa132
25%
81%
50%

5. Program Pencegahan Dengue
Tahun 1970-sekarang
Terlepas dari upaya-upaya pengendalian vektor yang sudah digiatkan, angka dengue di Indonesia terus bertambah dengan
dampak yang semakin meningkat dari waktu ke waktu (Harapan et al, 2019).
Kemenkes RI. Strategi Nasional Penanggulangan Dengue 2021-2025. Kemenkes RI. 2021

6. WHO Target 2030
“zero-death” of dengue
Indicator 2020
(baseline)
2023 2025 2030
• CFR due to dengue 0.80% 0.50% 0.50% 0%
• Number of countries
able to detect and
respond to dengue
outbreaks
10/128
(8%)
26/128
(20%)
64/128
(50%)
96/128
(75%)
• To reduce the burden
of the disease and its
incidence by 25%
3 100 900 3 million 2.75 million 2.35 million
Baseline in 2010-2020
World Health Organization. Ending the neglect to attain the Sustainable Development Goals A road map for
neglected tropical diseases 2021–2030. WHO 2020.

7. Riset dan Inovasi
Critical action to reach 2030 target
1. Continue developing preventive
vaccines for all at-risk populations.
2. Further develop the evidence base on
effectiveness of vector control
strategies.
3. Continue collaborating with
environmental sector and engineers to
reduce mosquito habitats.
World Health Organization. Ending the neglect to attain the Sustainable Development Goals A road map for neglected tropical
diseases 2021–2030. WHO 2020.

8. Strategi Nasional
dalam Penanggulangan Dengue
Indikator 2020
(baseline)
2021 2022 2023 2024 2025
• Proporsi kabupaten/kota
dengan incidence rate
(IR) dengue ≤49/100.000
penduduk
71.6% 75% 80% 85% 90% ≥90%
• Angka kematian akibat
dengue
0.7% 0.7% 0.7% 0.6% 0.6% 0.5%
Tujuan: Menurunkan beban kesehatan masyarakat akibat Dengue
Kemenkes RI. Strategi Nasional Penanggulangan Dengue 2021-2025. Kemenkes RI. 2021

9. Strategi Nasional Penanggulangan Dengue
Deskripsi Intervensi
(1) Identifikasi kebutuhan kajian, invensi,
inovasi, dan riset dan pelaksanaannya;
(2) Pengembangan kajian dan adopsi hasil
invensi, inovasi, dan riset dalam
program penanggulangan dengue;
(3) Pemanfaatan data yang berkualitas
serta integrasi sistem informasi untuk
pengambilan keputusan dalam
program penanggulangan dengue.
Ref. Kemenkes RI. Strategi Nasional Penanggulangan Dengue 2021-2025. Kemenkes RI. 2021

10. Dengue Virus Structure
• DENV consists of genes encoding the capsid
protein, membrane (M) protein, envelope (E)
protein, and non-structural (NS) proteins,
including NS1, NS2A, NS2B, NS3, NS4A, NS4B, and
NS5.
• E protein, which plays an important role in DENV
entry into the host cell, and NS1 which is exposed
to the host cell surface, are currently major
candidate Ags for use in a vaccine to induce
effective antibodies (Abs) and inhibit DENV
infection.
• In addition, NS3 and NS5, which have peptide
sequences displayed by human major
histocompatibility complex class I, are considered
major candidate Ags to induce the cellular
immune response against DENV infection.
DENV is a lipid-enveloped positive-strand RNA virus.
The basic functions of the DENV proteins considered the main
candidate Ags for dengue vaccine development.
Genomic profile of dengue virus (DENV) and structures of immature and mature DENV virions.
• Park J, Kim J, Jang Y-S. Current status and perspectives on vaccine development against dengue virus infection. J of Microbiol 2022;6(3):247-254

11. The potential pathogenic and therapeutic
roles of DENV-NS1
The DENV NS1 protein
could play dual roles
causing severe dengue
occurrence as well as to
ameliorate vascular
leakage and dengue
hemorrhage.
Wang W-H, Urbina AN, Lin C-Y, et al. Targets and strategies for vaccine development against dengue viruses. Biomed & Pharmocother 2021:144:112304

12. The mechanism and effect of antibody-
dependent enhancement (ADE)
The mechanism and effect of antibody-
dependent enhancement (ADE):
• The DENVs are detected and interact with anti-
envelope heterotypic antibodies but are not
neutralized.
• This virus-antibody complex is recognized by
Fcγ receptor (FcγR)-expressing immune cells
causing further infection of these immune
cells.
• This enhancement could result in
augmentation of virus propagation to further
cause severe dengue occurrence.
Wang W-H, Urbina AN, Lin C-Y, et al. Targets and strategies for vaccine development against dengue viruses. Biomed & Pharmocother 2021:144:112304

13. Antibody dependent enhancement (ADE)
(A) Primary infection with no previous vaccination.
DENV will enter macrophage through its cognate
receptor; however, most of the time, it will result
in mild disease, and sometime this could even be
symptomatic or with mild flu-like symptoms.
(A) DENV in the presence of neutralizing antibodies
for the same serotype. DENV will not be able to
enter the cells and establish infection.
(A) Cross-reactive antibodies from previous
unsuccessful dengue vaccine or dengue infection
with different serotypes will bind but not
neutralize the virus. This low-affinity binding will
facilitate the entry of the virus to the macrophage
through FC receptor resulting in increased viremia
leading to ADE.
Izmirly AM, Alturki Sana O, Alturki Sawsan O, et al. Challenges in Dengue Vaccines Development: Pre-existing Infections and Cross-Reactivity. Front. Immunol 2020;11:1055

14. Vaccine Targets and Strategies for
Dengue Vaccine Development
• Izmirly AM, Alturki Sana O, Alturki Sawsan O, et al. Challenges in Dengue Vaccines Development: Pre-existing Infections and Cross-Reactivity. Front. Immunol 2020;11:1055

15. Schematic diagram of various dengue vaccine
constructs
• Park J, Kim J, Jang Y-S. Current status and perspectives on vaccine development against dengue virus infection. J of Microbiol 2022;6(3):247-254

16. Tetravalent Immunization against Dengue
Efficacy Study (TIDES)
Primary endpoint : 80.2% overall efficacy against virologically confirmed dengue (12 months after 2nd dose)
Biswal, et al. N Engl J Med 2019; 381: 2009-19
Key secondary endpoint : 90.4% efficacy against VCD requiring hospitalization (18 months after 2nd dose)
Biswal S, et al. Lancet 2020; 395: 1423–1433
TAK-003 Clinical Trial (Takeda@)

17. TIDES secondary endpoint
Secondary VE endpoints were met for DENV1–3 but continued to be variable.
VE remained inconclusive against DENV-4 due to low case counts.
Secondary endpoint: VE by serostatus and serotype (18 months after second dose)
Biswal S, et al. Lancet 2020; 395: 1423–1433

18. Imunogenicity of seronegative baseline participant
• Average of Geometric Mean Titer (GMTs) still
above baseline
• Tetravalent seropositivity: 80,5% on 36 months
after second dose
• Stabilized GMT for DENV-1, DENV-3 and DENV-4
since 9 months after first dose
Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864

19. Safety profiles:
Local reaction at injection
site and systemic reaction
Frequency of injection site reactions and
solicited systemic events were similar in
both groups (12 months)
Summary of diary reported injection site reactions up to 7 days
and systemic adverse events up to 14 days after any
vaccination (subset of safety set data).
Data are presented as number of participants with events /
number of evaluated participants in the analysis set (% of
evaluated participants with events)
Biswal, et al. N Engl J Med 2019;281:2009–19

20. Serious Adverse Event (SAE)
Bulan 19 sampai 36 setelah dosis kedua
20
Jumlah (%) partisipan dengan SAE
Plasebo
(n=6.687)
TAK-003
(n=13.380)
Total
(n=20.071)*
SAEs – keseluruhan 234 (3,5) 386 (2,9) 620 (3,1)
Seronegatif 58/1.832 (3,2) 106/3.714 (2,9) 164/5.547 (3,0)
Seropositif 176/4.854 (3,6) 280/9.663 (2,9) 456/14.520 (3,1)
SAEs – berkaitan dengan vaksin 0 0 0
Mengarah pada penghentian studi 2 (<0,1) 5 (<0,1) 7 (<0,1)
Berkaitan dengan vaksin 0 0 0
Kematian 2 (<0,1) 5 (<0,1) 7 (<0,1)
Berkaitan dengan vaksin 0 0 0
# Dari akhir 18 bulan setelah dosis kedua hingga 36 bulan setelah dosis kedua
* Total termasuk 4 subyek yang mendapat produk investigasi yang berbeda karena kesalahan pada dosis pertama dan kedua sehingga
diesklusi dari kelompok placebo dan TAK-003
Seronegatif pada baseline: seronegatif terhadap kesemua empat serotipe dengue. Seropositif pada baseline: titer penetral resiprokal ≥10
terhadap satu serotipe dengue atau lebih
N adalah jumlah subyek pada set keamanan
1. Biswal at al, Three Years Efficacy of Takeda’s Tetravalent Dengue Vaccine Candidate I presented at CISTM17 congress 18-22 May, 2021. Congress abstract and presentation
2. Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864
• SAEs were reported by 2.9%
of TAK-003 recipients and
3.5% of placebo recipients in
the first half of part 3.
• None of the SAEs were
considered related to the
study vaccine.
• No important safety risks
have been identified during
the study.

21. Vaccine efficacy (95% CI) of TAK-003 in preventing virologically-confirmed dengue (VCD) and hospitalized VCD from the first dose to three years after
the second dose (approximately Month 39 after first dose; safety set data) by baseline serostatus.
Overall Efficacy against VCD and Hospitalized VCD: 36 months data
Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864
Data under the placebo and TAK-003 groups are presented as number of VCD or hospitalized VCD /number of evaluable participants
(number of VCD cases per 100 person years at risk)
The vaccine showed efficacy in both baseline seronegatives and baseline seropositives
(Virological confirmed dengue)

22. Cumulative VCD incidence until 36 months after second dose
Subgroup analysis based on baseline serostatus (safety set)
Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864
Per 100,000 vaccinated, prevention of
• 4664 cases in baseline seropositive
• 3977 cases in baseline seronegative

23. Cumulative incidence hospitalized VCD until 36 months after second dose
Subgroup analysis based on baseline serostatus (safety set)
Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864
Per 100,000 vaccinated, prevention of
• 1606 cases in baseline seropositives
• 1480 cases in baseline seronegatives

24. Subgroup
Placebo
(n=6687)
TAK-003
(n=13380)
VE
(95% CI)
VCD (-100 person per year) –based on severity
• Severe dengue (DCAC) 5 (<0,1) 3 (<0,1) 70,2 (−24,7, 92,9)
• DHF (WHO 1997 criteria) 13 (<0,1) 9 (<0,1) 65,4 (19,0, 85,2)
• Case that fulfill both criteria 1 2
Vaccine Efficacy to Severe Dengue
First dose until 36 months after second dose (safety set)
Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864
Overall VE against dengue hemorrhagic fever (DHF): 65.4% (19.0–85.2)
Overall VE against Dengue Case Severity Adjudication Committee (DCAC) defined severe dengue: 70.2% (−24.7 to 92.9)

25. Long-Term Exploratory Analysis of TIDES
(54 months data)
• TAK-003 demonstrated 84.1% vaccine efficacy (VE) (95% CI: 77.8, 88.6) against
hospitalized dengue,
• 85.9% VE (78.7, 90.7) in seropositive individuals
• 79.3% VE (63.5, 88.2) in seronegative individuals.
• TAK-003 also demonstrated overall VE of 61.2% (95% CI: 56.0, 65.8) against virologically-
confirmed dengue (VCD),
• 64.2% VE (58.4, 69.2) in seropositive individuals
• 53.5% VE (41.6, 62.9) in seronegative individuals.
• TAK-003 was generally well tolerated, and there were no important safety risks identified.
• No evidence of disease enhancement was observed over the 54-month follow-up
exploratory analysis.
25
These data were presented on June 9, 2022, at the 8th Northern European Conference on Travel Medicine (NECTM8)
https://www.takeda.com/newsroom/newsreleases/2022/takedas-dengue-vaccine-candidate-provides-continued-protection-against-dengue-fever-through-4.5-years-in-pivotal-clinical-trial/

26. Take home message
• Kasus dengue di Indonesia meningkat pada awal tahun 2022
• Data seroprevalens dengue menunjukkan Indonesia termasuk
endemik tinggi, anak umur < 5 tahun setidaknya telah mengalami
infeksi dengue satu kali
• Untuk mencapai zero death dengue 2030 diperlukan
pengembangan “Integrated vector management” yang efektif dan
pengembangan vaksin bagi semua populasi yang berisiko
• Pengembangan vaksin dengue tetap berlanjut, dengan harapan
dengan pemberian vaksin dapat mencegah infeksi dengue tanpa
dipengaruhi oleh paparan dengue sebelumnya
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