Daily Clinical Practice of Dengue Vaccine in

Healthy and Comorbid Patients

Nina Dwi Putri

Department of Child Health
Faculty of Medicine Universitas Indonesia
Cipto Mangunkusumo Hospital
Universitas Indonesia Hospital
dr. Nina Dwi Putri, Sp. A(K), MSc. (TropPaed)
APPOINTMENT
● Lecturer in pediatric infectious disease and tropical pediatrics Universitas Indonesia
● Pediatric ID consultant in Cipto Mangunkusumo National Referral Hospital
● Pediatric ID consultant Universitas Indonesia Hospital
EDUCATION
● Master of tropical pediatric, Liverpool School of Tropical Medicine, United Kingdom,
2018/19
● Executive fellowship in Pediatric Infectious Disease, The Children hospital at Westmead,
Sydney - 2018
● Pediatric ID consultant training, Universitas Indonesia, 2015-2017
● Clinical fellowship in infectious disease for Institute of Infectious Disease and
Epidemiology, National Center of Infectious Disease, Tan Tock Seng Hospital, Singapore
- 2014
● Pediatric Residency Training, Universitas Indonesia, 2007 -2012
● Medical Doctor, Universitas Indonesia, 2000-2006
ORGANIZATION
● COVID-19 Taskforce of IDAI and PB IDI COVID-19
● Secretary of Scientific Affair of Indonesia Pediatric Society, 2017-2020
● Head of book division of Indonesia Pediatric Society Publishing Unit, 2015-2020
AWARD
● Thomas Mark Award, UK
● Endeavour Award, Australia
● Asia Pacific Economic Cooperation Scholarship, Singapore
Outline

• Dengue Infection
• Risk Factor of Severe Dengue
• Dengue Vaccination Recommendations
 Dengue Etiology

Arboviruses (arthropod-
borne viruses)

Transmission : Aedes 
Ae. aegypti (primer)

4 DENV serotypes
(DENV-1, DENV-2,
DENV-3, DENV-4)

World Health Organization. Dengue vaccine : WHO position paper – September 2018. 2018. No 36, 2018, 93, 457–476
 Dengue Fever

80 %

1. World Health Organization. Dengue vaccine : WHO position paper – September 2018. 2018. No 36, 2018, 93, 457–476
2. World Health Organization. Dengue guidelines for diagnosis, treatment, prevention, and control. France. 2009
 Dengue Classification and Clinical Presentation

Wang, W.-H., Urbina, A. N., Chang, M. R., Assavalapsakul, W., Lu, P.-L., Chen, Y.-H., & Wang, S.-F. Dengue hemorrhagic fever – A systemic literature review of current perspectives on pathogenesis, prevention and control. Journal of Microbiology,
Immunology and Infection 2020. doi:10.1016/j.jmii.2020.03.007
 Risk Factors of Dengue Hemorrhagic Fever

Wang, W.-H., Urbina, A. N., Chang, M. R., Assavalapsakul, W., Lu, P.-L., Chen, Y.-H., & Wang, S.-F. Dengue hemorrhagic fever – A systemic literature review of current perspectives on pathogenesis, prevention and
control. Journal of Microbiology, Immunology and Infection 2020. doi:10.1016/j.jmii.2020.03.007
 Comorbidities also affect dengue severity
The presence of comorbidities including diabetes, hypertension
and renal insufficiency are associated with severe dengue
disease and death in adults1–4
Summary of comorbidities recorded in hospitalised dengue cases aged 9-
45 years at admission (Brazilian Hospital Information System of the
Unified Health System (SIH/SUS), 2008-2015)
Children, secondary infection, diabetes and renal
disease(s) as important predictors of severe dengue.

Patients with dengue infection + DM or DM &

The case fatality rate from hospitalized dengue is 11 times higher in Hypertension have a higher risk of developing severe
patients with common comorbidities than in patients with no dengue
comorbidities (3.07% vs 0.27%, p<0.001)5 Patients with dengue infection + comorbidity need
intensive monitoring and treatment
8 1. Pang, et al. Sci Rep. 2017;7:39872, 2. Guo, et al. Front Cell infect Microbiol. 2017;7:317, 3. Lee, et al. J Microbiol Immunol Infect. 2006;39:121–9, 4. Wei, et al. Am j Trop Med Hyg, 2016;95:322–7,
5.Werneck, et al. Mem Inst Oswaldo Cruz, 2018;113:e180082
 Dengue in Elderly and Pregnancy have a higher risk of severe dengue

Elderly dengue patients present atypically and are at

higher risk of DHF, SD and HAI. Aside from dengue
severity, age, co-morbidity and HAI were associated with
longer hospital stay

Dengue in pregnancy increases the risk of pre-eclampsia,

Dengue Hemorrhagic Fever (DHF), fetal distress, preterm
delivery, Caesarean delivery, and maternal mortality.
Vertical transmission, intrauterine growth restriction, and
stillbirth are possible sequelae of dengue in fetuses

Patients with dengue infection + DM or DM & Hypertension

have a higher risk of developing severe dengue and need
intensive monitoring and treatment
 Ratnam 2013
Dengue 3%
(1-3%)
 Dengue and Post Infection Fatigue

Up to one-third of dengue patients may be have post-infection fatigue

• 60 patients had fatigue (51 [32%] dengue, 9 [9%] non-

dengue patients), with a higher risk in females
• Dengue patients had a significantly higher risk of fatigue at 2
months after the acute infection (RR: 4.93; 95% CI: 2.3–
10.4; p<0.001)
• Fatigue scores for female dengue patients was significantly
higher compared with male patients (RR: 2.45; 95% CI:
1.24–4.86, p<0.05).
• Diabetes patients with severe dengue correlated with a
higher risk of developing post infection fatigue

Sigera PC, Rajapakse S, Weeratunga P, et al. Dengue and post-infection fatigue: findings from a prospective cohort—The Colombo Dengue Study. Trans R Soc Trop Med Hyg 2020; 0: 1–
8.
 BPOM issued a permit for dengue vaccination on August 19,
2022
The Dengue vaccine is indicated
for dengue prevention caused by
all dengue serotypes in
individuals aged 6 to 45 years

The dengue vaccination must

comply with official national
recommendations.

Serostatus testing is NOT required before vaccination

Ringkasan Karakteristik Produk TAK-003 yang telah disetujui BPOM. 2022

Phase 3 TIDES Trial to Assess the Safety and Efficacy of
Tetravalent Dengue Vaccine (TDV) in a Broad Population
Broad patient population Trial design met WHO
20,000 8 4/4 recommendations for a second-
children & endemic Includes all generation dengue vaccine
adolescents countries four serotypes
– 4.5 years of follow-up

Study Design Patients stratified by serostatus*

Primary endpoint – prevention of
0 3 4 15 21 Month 57
symptomatic dengue cases @ 12 months
12 months 6 months 36 months
Key secondary endpoint – reduction in
Part 1 Part 2 Part 3
Primary efficacy
hospitalizations @ 18 months
endpoint
Exploratory endpoint – sustained
Secondary efficacy endpoints
preventions of symptomatic dengue and
reduction in hospitalization @ 4.5 years
Active surveillance Modified active surveillance
*Serostatus – is whether a patient has had a prior infection or not

Takeda. Data on file.

13
 PHASE 3 TIDES TRIAL RESULTS THROUGH 4.5 YEARS
DEMONSTRATED IMPORTANT VACCINE FEATURES
PRIMARY ENDPOINT SECONDARY ENDPOINT EXPLORATORY ANALYSIS (UP TO 4.5 YEARS)

OVERALL EFFICACY HOSPITALIZATION OVERALL EFFICACY HOSPITALIZATION SAFETY PROFILE

Vaccine efficacy against virologically Vaccine efficacy against dengue Vaccine efficacy against virologically Vaccine efficacy against dengue Safety profile
confirmed dengue (VCD) hospitalization confirmed dengue (VCD) hospitalization

81.6% 93.5% 64.8% 86.5%

(95%CI:74.3% - 86.8%, p<0,01) (95%CI:86.5%, 96.9%, p<0,01) (95%CI:59.4%, 69.%, p<0,01) (95%CI:80.3%, 90.7%, p<0,01) Well-tolerated overall safety
In pivotal phase 3 clinical TAK-003 showed overall Up to 4.5 years after the In long-term exploratory profile with no important
studies, dengue vaccine TAK- efficacy at 18 months after second dose, TAK-003 analysis. The vaccine identified safety risks.
003 showed overall efficacy the second dose showed an overall VE of showed a sustained
against VCDs at 12 months after 64.8% in preventing VCD1 significant reduction in No screening needed prior
the second dose1,2 hospitalizations due to vaccination
VCDs for up to 4.5 years1
*Data in children & adolescents 6-16 years

14 1. Ringkasan Karakteristik Produk Qdenga yang telah disetujui BPOM. 2023 2. Biswal S, Reynales H, Saez-Llorens X, et al. Efficacy of a tetravalent dengue vaccine in healthy children and adolescent. N Engl J Med. 2019; 381(21):2009-2019. doi:10.1056/NEJMoa1903869. 3.
EMA18: European Medicines Agency. European public assessment report: Dengvaxia. 2018. Accessed 2023. https://www.ema.europa.eu/en/documents/assessment-report/dengvaxia-epar-public-assessment-report_en.pdf
 TAK-003: Immunogenicity in the Adults vs Children Population are
Non-Inferior
Non-inferiority for given serotype will be concluded if upper bound of 95% CI for the GMR is below 2.
DEN-301 (Age 4-16) DEN-304 (Age 18-60)
DENV serotype Visit Adjusted GMT (95% CI) Adjusted GMT (95% CI) GMR (95% CI)
N=702 N=379
Month 4 184.2 (165.9, 204.6) 268.1 (233.5, 307.9) 0.69 (0.58, 0.82)
DENV-1
Month 9 87.8 (77.8, 99.2) 141.7 (120.9, 166.1) 0.62 (0.51, 0.76)

Month 4 1730.2 (1603.1, 1867.3) 2956.9 (2673.4, 3270.4) 0.59 (0.52, 0.66)
DENV-2
Month 9 929.4 (851.7, 1014.1) 1403.3 (1251.9, 1572.9) 0.66 (0.57, 0.76)

Month 4 228 (209.2, 248.5) 128.9 (115.0, 144.4) 1.77 (1.53, 2.04)
DENV-3
Month 9 71.7 (65.4, 78.6) 73.1 (64.8, 82.4) 0.98 (0.84, 1.14)

Month 4 143.9 (132.8, 156.0) 137.4 (123.5, 152.9) 1.05 (0.92, 1.20)
DENV-4
Month 9 64.0 (58.2, 70.4) 63.5 (56.0, 71.9) 1.01 (0.86, 1.18)

A comparable immune response against all 4 DENV serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) in
baseline seronegative adults in the DEN-304 trial versus children and adolescents in the DEN-301 trial.
These findings support extrapolation of the efficacy of the TAK-003 vaccine observed in children and
adolescents in DEN-301 to an adult population

Rivera
15 L, et al. "Three-year Efficacy and Safety of Takeda’s Dengue Vaccine Candidate (TAK-003)." Clinical Infectious Diseases 75.1 (2022): 107-117
 TAK-003 is Recommended by IDAI

TAK 003 is given in 2 doses, 3 months apart, aged 6 - 18 years old

Sitaresmi MN, Soedjatmiko, Gunardi H, et al. Jadwal Imunisasi Anak Usia 0 – 18 Tahun Rekomendasi Ikatan Dokter Anak Indonesia Tahun 2023. Available at
https://saripediatri.org/index.php/sari-pediatri/article/view/2352 Accessed 14 September 2023
Satgas Imunisasi Dewasa PAPDI. Jadwal Imunisasi Dewasa. Tersedia di https://satgasimunisasipapdi.com/jadwal-imunisasi-dewasa/ Diakses 14 September 2023
 TAK-003 is Recommended by PAPDI

Dengue vaccine is also recommended for comorbid population i.e

Dengue vaccine is given in 2 doses, 3 months COPD, diabetes, heart disease, chronic alcoholic, renal failure,
apart, aged 19-45 years old chronic liver disease, healthcare professionals

Sitaresmi MN, Soedjatmiko, Gunardi H, et al. Jadwal Imunisasi Anak Usia 0 – 18 Tahun Rekomendasi Ikatan Dokter Anak Indonesia Tahun 2023. Available at
https://saripediatri.org/index.php/sari-pediatri/article/view/2352 Accessed 14 September 2023
Satgas Imunisasi Dewasa PAPDI. Jadwal Imunisasi Dewasa. Tersedia di https://satgasimunisasipapdi.com/jadwal-imunisasi-dewasa/ Diakses 14 September 2023
PERDOKI has released Immunization Guideline for Protection and Workers
Productivity Improvement including Dengue Vaccine
Summary

• Some risk factor and predictor related to severe Dengue infection including age, comorbidity,
pregnancy, virus type and secondary infections should be considered in implementation of
Dengue vaccination
• TAK-003 is recommended for children and adults aged 6 to 45 years, administered in two doses
three months apart with no screening required prior to vaccination
• Indonesian Pediatric Society (IDAI) and Indonesian Society of Internal Medicine (PAPDI) have
updated their immunization schedules to include TAK-003.
• Dengue vaccine has been included in PERDOKI’s vaccine recommendation for workers in
agricultural/plantation/forestry sector, workers in endemic areas and construction sites.
 Thank
Thank you
you