Immunogenicity of an Intradermal Qdenga Vaccine Among Healthy Volunteers: A Pilot Study
Phase: EARLY_PHASE1
Conditions: Dengue
Sponsor: Prince of Songkla University

 
Study Document Cover Page 
Official Study Title: 
Immunogenicity of an intradermal live attenuated tetravalent dengue vaccine among healthy volunteers: 
A pilot study 
NCT Number: NCT06837116 
Document Type: Study Protocol 
Document Date: 16-11-2025 
Sponsor / Institution: 
Faculty of Medicine, Prince of Songkla University 
Principal Investigator: 
Assoc. Prof. Sarunyou Chusri, M.D. 
Division of Infectious Diseases, Department of Internal Medicine 
Faculty of Medicine, Prince of Songkla University 
Email: sarunyouchusri@hotmail.com 
Co-Investigators: 
Nawamin Pinpathomrat, M.D. 
Pisud Siripaitoon, M.D. 
Narongdet Kositpantawong, M.D. 
Siripen Kanchanasuwan, M.D. 
Sorawit Chittrakarn, M.D. 
Tawin Khaimook, M.D. 
Supattra Uppanisakorn 
 
 
 
 
 
 
 

 
1.  Thai title 
การศึกษานำร่องการทดสอบภูมิคุ้มกันต่อเชื้อไวรัสเดงกี่หลังได้รับวัคซีนไข้เลือดออกเชื้อเป็นอ่อนฤทธิ์ชนิดสี่สายพันธ์เข้าผิวหนัง
ในกลุ่มอาสาสมัครสุขภาพดี 
2.  English title 
Immunogenicity of an intradermal live attenuated tetravalent dengue vaccine among healthy volunteers: 
A pilot study 
3. Keywords 
English:  Dengue, Intradermal vaccination, Immunogenicity, T cell response, Tetravalent dengue   
vaccine 
4. Researcher/ Sub-investigator/ Co-investigator/ Affiliation  
1. Associate Professor Sarunyou Chusri, M.D. 
Position: Principal Investigator 
Affiliation: Division of Infectious Diseases, Department of Internal Medicine, Faculty of Medicine, 
Prince of Songkla University 
Office Phone: +66-74-451452 
Mobile Phone: +66-89-7340446 
Email: sarunyouchusri@hotmail.com 
Role in the Study: Drafting the study protocol, conducting the study, screening participants, 
monitoring participant safety, preparing reports, and manuscript publication. 
 
2. Assistant Professor Nawamin Pinpathomrat, M.D., Ph.D. 
Position: Co-Investigator 
Affiliation: Department of Biomedical Sciences, Faculty of Medicine, Prince of Songkla University 
Office Phone: +66-74-451180 
Mobile Phone: +66-64-8142071 
Email: nawamin.p@psu.ac.th 
Role in the Study: Drafting the study protocol, conducting the study, laboratory analysis, data 
analysis, report writing, and manuscript publication. 
 
3. Assistant Professor Pisud Siripaitoon, M.D. 
Position: Co-Investigator 

 
Affiliation: Department of Internal Medicine, Faculty of Medicine, Prince of Songkla UniversityOffice 
Phone: +66-74-451456 
Mobile Phone: +66-89-6559945 
Email: Grippen45@gmail.com 
Role in the Study: Drafting the study protocol, conducting the study, data analysis, report writing, 
and manuscript publication. 
 
4. Assistant Professor Narongdet Kositpantawong, M.D. 
Position: Co-Investigator 
Affiliation: Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University 
Office Phone: +66-74-455000 
Mobile Phone: +66-81-5991929 
Email: narongdet032@gmail.com 
Role in the Study: Drafting the study protocol, conducting the study, data analysis, report writing, 
and manuscript publication. 
 
5. Associate Professor Siripen Kanchanasuwan, M.D. 
Position: Co-Investigator 
Affiliation: Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University 
Office Phone: +66-74-455000 
Mobile Phone: +66-84-2121234 
Email: kaymed29@yahoo.com 
Role in the Study: Drafting the study protocol, conducting the study, data analysis, report writing, 
and manuscript publication. 
 
6. Sorawit Chittrakarn, M.D. 
Position: Co-Investigator 
Affiliation: Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University 
Office Phone: +66-74-455000 
Mobile Phone: +66-93-5833126 
Email: Sorawit.c@psu.ac.th 
Role in the Study: Drafting the study protocol, conducting the study, data analysis, report writing, 
and manuscript publication. 
 
 

 
7. Tawin Khaimook, M.D. 
Position: Co-Investigator 
Affiliation: Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University 
Office Phone: +66-74-455000 
Mobile Phone: +66-84-6912946 
Email: tawin.khaimook@gmail.com 
Role in the Study: Drafting the study protocol, conducting the study, participant screening, 
monitoring participant safety, report writing, and manuscript publication. 
 
8. Mrs. Supattra Uppanisakorn 
Position: Advanced Practice Nurse 
Affiliation: Clinical Research Center, Songklanagarind Hospital 
Office Phone: +66-74-451735 
Mobile Phone: +66-85-6781034 
Email: poohsupattra@gmail.com 
Role in the Study: Conducting study procedures, blood collection, vaccine administration, data 
documentation, participant follow-up, and coordinating EC documentation. 
 
5. Details of proposal 
 
5.1 Background 
 
Dengue fever, caused by the dengue virus (DENV), represents a significant global health challenge, 
particularly in tropical and subtropical regions. This disease affects millions of individuals annually, 
resulting in severe morbidity and a substantial economic burden. Advanced age is a significant risk factor 
for increased severity and mortality associated with this condition1, predicting an escalating impact in the 
future. In the absence of specific antiviral treatments, the development and implementation of effective 
vaccination strategies are crucial in mitigating the impact of dengue fever.  
 
Qdenga, a live attenuated tetravalent dengue vaccine traditionally administered subcutaneously, has 
shown promising results in conferring immunity against all four dengue serotypes2, this one also not need 
to check for previous infection as concerning of enhancing antibody as the previous Dengvaxia vaccine, 
promoting more opportunity.  
 
 

 
5.2 Study setting background 
 
Intradermal vaccination is an established method known to enhance immunogenicity by targeting the 
rich network of antigen presenting cells present in the dermis3, WHO have done a literature review in 
2009 for studies about intradermal injection proposed that a fractional ID dose can induced adequate 
immune responses in healthy persons for variable type of vaccines4, including those for rabies, yellow 
fever, poliomyelitis, seasonal influenza and there also be more others recent studies focusing on the 
COVID-19 vaccination5-7 as vaccine inequity remains a challenge across the globe.  
5.3 Rationale 
 
As in the setting of low- to middle-income countries, to demonstrating that lower doses of vaccine 
via intradermal route can still elicit robust immune responses, thereby lowering the overall cost of 
vaccination might be particularly meaningful ,with possible extra benefit of experiencing fewer side effects 
or risk of allergy5, 8. This study goal is to explores the potential of intradermal administration of Qdenga, 
hypothesizing that a lower dose via this route could achieve adequate immunogenicity compared to the 
standard subcutaneous administration, thus offering a cost-effective alternative particularly in low-
resource settings where dengue is most prevalent.  
 
5.4 Objectives 
Primary Objectives 
1. To evaluate the antibody response to dengue virus following administration of the second dose of 
QdengaTM via the intradermal route. 
2. To evaluate the T-cell response (CD4 and CD8) to dengue virus following administration of the second 
dose of QdengaTM  via the intradermal route. 
Secondary Objective 
1. To assess the safety and reactogenicity of intradermal administration of Qdenga. 
 
5.5 Literature review 
Dengue fever, attributable to the dengue virus, represents a substantial global health concern. 
The advent of vaccines such as Qdenga and Dengvaxia has demonstrated potential in conferring immunity 

 
against all four serotypes of the dengue virus. However, given the higher prevalence of dengue fever in 
resource-limited tropical regions, it is crucial to explore cost-reduction strategies. Intradermal injection, a 
previously successful dose-sparing technique, offers one such strategy. Nonetheless, the efficacy of 
intradermal administration for the newly developed Qdenga vaccine remains uncertain and warrants 
further investigation. 
Study on the immunogenicity of the Qdenga vaccine, given subcutaneously, have shown 
promising results. One randomized, placebo-controlled Phase 2 study9 involving 148 participants aged 1.5 
to 45 revealed seropositivity rates at month 36 of 97.3%, 98.7%, 88.0%, and 56.0% for DENV-1, -2, -3, and 
-4, respectively. Notably, seropositivity for DENV-4 varied significantly based on initial serostatus, with 
89.5% in seropositive individuals compared to 21.6% in seronegative individuals. No vaccine-related 
serious adverse events (SAEs) were reported. The study demonstrated the persistence of neutralizing 
antibody titers and the Qdenga vaccine's tolerability over three years in both children and adults living in 
dengue-endemic regions.  
A key concern with the dengue vaccine is the potential side effects, including transient vaccine 
viremia. After receiving the Qdenga vaccine, 49% of previously uninfected participants and 16% of those 
previously infected with dengue experienced vaccine viremia10. This viremia typically began in the second 
week post-vaccination, lasted an average of four days, and was associated with mild to moderate 
symptoms such as headache, joint pain, muscle pain, and rash in some subjects. During this period, 
dengue diagnostic tests may yield positive results, making it difficult to distinguish between vaccine 
viremia and wild-type dengue infection. A study on IgG, IgM, and nonstructural protein 1 (NS1) response 
profiles post-Qdenga vaccination indicated that IgM and IgG profiles within 30 days of vaccination were 
similar to those observed during natural dengue infections, though no NS1 antigen was detected11. As 
previously proposed that lower dose of vaccine might be associated with possible extra benefit of 
experiencing fewer side effects or risk of allergy5, 8, intradermal reduced dosed sound compelling. 
Qdenga vaccine was also called TAK-003/DENvax in previous study, it was based on a live-
attenuated DENV-2 strain (PDK-53-V) in which the premembrane (prM) and envelope (E) genes have been 
replaced by the homologous genes from each one of the four DENV serotypes12. The recommendation 
for using the subcutaneous route in dengue vaccine administration is based on findings from certain Phase 
I studies. One such study assessed the safety and immunogenicity of a recombinant live attenuated 
tetravalent dengue vaccine (DENvax) in 96 flavivirus-naive healthy adults in Colombia. Participants in this 
study were randomized to receive either a high-dose formulation of DENvax or a placebo via 

 
subcutaneous or intradermal injection. The study results indicated that both intradermal and 
subcutaneous routes elicited tetravalent dengue immune responses. However, the subcutaneous route 
was associated with a lower incidence of local adverse events compared to the intradermal route, 
although the difference was not statistically significant.13.  
Another study evaluated the safety and immunogenicity of an early low-dose tetravalent dengue 
vaccine candidate (LD-TDV), which uses an attenuated serotype 2 backbone, administered intradermally 
either with an injector device (PharmaJet) or a needle-syringe in 67 subjects. The findings indicated that 
the intradermal administration of LD-TDV was well tolerated, with no significant safety concerns, and 
induced an immune response against all four dengue serotypes14. The overall tetravalent seroconversion 
rates were 13.8% at Day 28 and 31.0% at Day 118, comparable to the previously reported 25% 
seroconversion rate for low-dose TDV given intradermally in 72 flavivirus-naive adults. Local reactions, 
such as induration (91.7% vs. 12.5%; P < .0001) and pruritus (50% vs. 8.3%; P = .0034), were more 
frequent following intradermal vaccination compared to subcutaneous administration. Most of these 
reactions were mild and resolved within one day15. 
This study aims to ensure the safety of vaccine recipients by comparing the administration of a 
second dose via the intradermal (ID) route after an initial subcutaneous (SC) dose with a control group 
receiving both doses subcutaneously (SC-SC). Previous research in Thailand on COVID-19 vaccines also 
evaluated the safety and immunogenicity of fractional (1/5th or 1/6th) doses of homologous ChAdOx1 or 
BNT162b2 administered intradermally following an initial intramuscular (IM) dose, demonstrating safety 
and immunogenicity16. Based on this, the study hypothesizes that intradermal administration of fractional 
doses of the Qdenga vaccine after an initial SC dose will be immunogenic and have acceptable systemic 
adverse effects, with potential utility as a booster in the future. 
The potential of intradermal vaccination to maintain or enhance immunogenicity while reducing 
the required dose has been highlighted in several reviews4, 17. This method could lower costs and improve 
vaccine accessibility in low-resource settings. However, further research is needed, as no randomized 
studies have yet evaluated both humoral and cell-mediated immune responses to intradermal Qdenga 
vaccination. 
 
 

 
5.6 Conceptual framework 
A new dengue vaccine, QdengaTM, has recently become available in Thailand. As a live-attenuated 
vaccine, it does not require pre-vaccination serological screening for dengue immunity, unlike DengvaxiaTM. 
However, access to QdengaTM remains limited due to its high cost and the fact that it is not yet 
reimbursable for the general population. The vaccine is designed for subcutaneous administration and is 
given as a two-dose series, with the second dose administered three months after the first. 
In theory, intradermal administration may elicit comparable immune responses while using a lower 
vaccine dose, owing to the high density of antigen-presenting cells in the dermal layer. Based on this 
rationale, investigators from multiple departments within the Faculty of Medicine have initiated a 
collaborative study to evaluate the immunogenicity and safety of intradermal QdengaTM administration in 
healthy volunteers. Immune responses will be assessed at baseline, 30 days after the first dose, and 30 
days after the second dose. All participants will receive the first dose subcutaneously as per standard 
practice, then be randomized to receive the second dose either subcutaneously or intradermally. 
This study aims to enhance understanding of the immune response elicited by QdengaTM given via 
different administration routes and to generate data that may inform future vaccine implementation 
strategies and potential dose-sparing approaches. 
 

 
5.7 Research methodology 
5.7.1 Study Design 
Prospective observational study 
 
5.7.2 Study Setting 
Clinical research center, Prince of Songkla university 
 
5.7.3 Study samples 
5.7.3.1 Inclusion Criteria 
1. Thai adult aged 18-60 years with positive dengue IgG from screening test, who not 
previously received dengue vaccine. 
2. The subjects are able to and willing to comply with the requirements of the clinical 
trial program and could complete the 3-month follow-up of the study. 
3. Individuals who are in good health condition at the time of entry into the trial as 
determined by 
medical history, physical examination and clinical judgment of the investigator and 
meet the requirements of immunization 
4. The subject can provide with informed consent and sign informed consent form 
 
5.7.3.2 Exclusion criteria  
1. Have a medical history or family history of convulsion, epilepsy, encephalopathy and 
psychosis. 
2. Be allergic to any component of the research vaccines or used to have a history of 
hypersensitivity or serious reactions to vaccination. 
3. Women with positive urine pregnancy test, pregnant or breast-feeding, or have a 
pregnancy plan within six months. 
4. Have acute infectious diseases, including dengue infection 
5. Have severe chronic diseases or condition in progress cannot be controlled.  
For example, poor controlled DM and uncontrolled HT. 
6. Have the history of urticaria 1 year before receiving the investigational vaccine. 
7. Have needle sickness. 

 
8. Have the history of immunosuppressive therapy, cytotoxic therapy or systemic 
corticosteroids 
9. Have received blood products within 6 months before injection of investigational 
vaccines. 
10. Not be able to follow the protocol or not be able to understand the informed 
consent according to the researcher's judgment, due to various medical, psychological, 
social or other conditions. 
11. Recent administration within 1 months or planned to get any lived attenuated 
vaccine within the study period. 
 
5.7.4 Subject withdrawal criteria 
1. The participant chooses to withdraw from the study at any time. 
2. The study is discontinued at the discretion of the investigator if continuation poses a 
potential risk to the participant. 
3. The participant wishes to receive other vaccines (e.g., pneumococcal vaccine, zoster 
vaccine) within 30 days after receiving the study vaccine. 
4. The participant develops anaphylaxis or any severe adverse event following the first 
dose of the vaccine. 
 
5.7.5 Study termination criteria 
1. The study procedures conflict with national or governmental policies. 
2. New scientific evidence emerges, indicating that continuation of the study provides no 
meaningful benefit.  
3. Intradermal vaccination results in severe local adverse events—such as abscess, 
granulomatous reactions, or skin necrosis—in more than 10% of study participants. 
 
5.7.6 Sample size calculation 
In this study, a total sample size of 24 participants will be used, allocated equally into two 
groups of 12 participants each. Based on the recommendation by Julious13, a sample size of 
12 subjects per group is considered adequate to achieve reasonable precision for preliminary 
estimates in a pilot study. 

 
 
5.7.7 Sampling 
   - None 
 
5.7.8 Study variables and their definition 
Independent variables 
- Technique of vaccination: subcutaneous vs. intradermal 
- Sex 
- Age 
Dependent variables 
- ELISA: Antibody level for dengue at day 0, 30, 120 
- ELISpot: T cell responses against dengue antigens at day 0, 30, 120 
- Adverse event following vaccine (AEFI) 
 
5.7.9 Questionnaire/Instrument/Tool/Machine 
 
Immunological study  
 
Blood collection 
 
- 
15 ml of blood samples were taken before booster vaccination then 30 days after 
vaccination. The blood was split into 1 clotted blood tube and 2 heparinized tubes.  
 
Sample preparation 
 
- 
The sample preparation process will be done in the Biosafety Level 2. Laboratory 
staff will wear adequate PPEs as per BSL2 protocol. 
 
- 
The samples will always be opened in BSL2 cabinet.  
 
- 
The heparinized blood was spun as per PBMC separation protocol. The PBMCs 
were stored in liquid nitrogen for further experiments while the plasma samples kept at 
-80 c as well as serum from clotted blood. 
 
- 
Leftover samples will be kept for 5 years for relevant immunological analysis then 
will be discharge as per BSL 2 protocol. 
 
Antibody analysis 
 
- 
Detection of dengue-specific human Abs by ELISA 
 
- 
Mixtures of all four DENV serotypes were captured onto a MAXISORP immunoplate 
(NUNC) coated with mouse anti-E antibody (4G2) or anti-NS1 antibody (NS1-F3). DENV 
captured wells were then incubated with B cell line (BCL) culture supernatants followed 

 
by alkaline phosphatase (AP)-conjugated anti-human IgG Abs. The reaction was visualized 
by the addition of PNPP substrate. The reaction was stopped with NaOH. 
 
 
T cell responses 
 
ELISpot assay  
 
Briefly, PBMCs were added to polyvinylidene difluoride–backed plates (Millipore) 
precoated with a monoclonal antibody to IFN-γ (1-DIK; MABTECH). Peptides were then 
added at a final concentration of 10 μM and the PBMCs were cultured overnight. Cells 
were discarded and spots were revealed by incubation with biotinylated monoclonal 
antibody to IFN-γ (MABTECH) followed by streptavidin-conjugated alkaline phosphatase 
and substrate. The spots were counted using an AID-ELISpot Reader (Autoimmun 
Diagnostika). The number of specific T-cell responders was calculated after subtracting 
negative control values. 
 
Peptides  
 
- 
15-mer peptides overlapping by 5 amino acids corresponding to sequences of 
dengue serotype 2 strain 16681 (CprM, E, NS1, NS2, NS3, NS4, and NS5) and to the NS3 
sequences of dengue serotype 1 strain Hawaii, dengue serotype 3 strain H87, and 
dengue serotype 4 strain H241 were synthesized to >80% purity (Sigma Aldrich). 
Lyophilized peptides were resuspended in dimethyl sulfoxide (DMSO; Sigma) at 80 
mg/mL for peptide mixtures. The overlapping peptides were grouped together in pools 
corresponding to individual dengue proteins (dengue 2: CprM-26, E-97, NS1-71, NS2-70, 
NS3-123, NS4-70, NS5-95, dengue 1 NS3-124, dengue 3 NS3-124, and dengue 4 NS3-124). 
The final concentration of any single peptide was 2 μg/mL, and the final concentration 
of DMSO was <1% in all experiments. 
5.7.10 Data collection 
- Participant information will be recorded in a case record form (CRF). Personal identifiers 
such as name, address, date of birth, and national identification number will not be 
recorded. Only the hospital number will be documented for follow-up purposes, and 
this will be removed and replaced with a study code when transferred into the 
electronic database. All paper CRFs will be stored in a locked cabinet until the 
completion of the study. 

 
- Immunological study data will be analyzed and stored in electronic files. The linkage 
between laboratory results and participant information will occur only at the final stage 
of the study. 
Study flow 
 
Study procedure 
Study period 
Screening 
Treatment  
Vaccine dose 1 
Treatment  
Vaccine dose 2 
Follow up 
Day/week 
    Day 0 to -7 
        Day 0 
   Day 90 ± 3 days 
Day 30 ± 3 day 
  Day 120 ± 3 days 
Informed consent, 
medical history 
X 
 
 
 
 
Contraceptive 
counselling 
X 
 
 
 
 
Screen dengue IgG 
X 
 
 
 
 
Review of Inclusion/ 
exclusion criteria 
 
X 
X 
 
 
Physical examination 
 
X 
X 
 
 
Body Weight/ Height/ 
Vital sign 
 
X 
X 
 
 
Concomitant  
medication check 
 
X 
X 
 
 

 
 
Arms and Interventions:  
Arm 1: subcutaneous Qdenga for 1st vaccination then intradermal Qdenga for 2nd vaccination 
Arm 2: subcutaneous Qdenga for 1st vaccination then subcutaneous Qdenga for 2nd vaccination 
 
5.7.11 Ethical Consideration 
• Informed consent process 
1. The research team will announce and publicize the study through the Line account 
(@psucrc) and the Clinical Research Center website to invite individuals who may be 
interested in participating. Participants may contact the investigators or study nurses at any 
time if they have questions or concerns. 
2. Individuals who wish to participate may register their interest through the Line account 
(@psucrc) or by emailing poohsupattra@gmail.com 
3. The study nurse will provide the participant information sheet and invitation documents 
through a method convenient for the potential participant (e.g., email or Line). Those who 
agree to participate will sign the consent invitation document and return it to the Clinical 
Research Center. 
4. The study nurse will schedule study visits according to the protocol. Appointments will be 
arranged on weekends or public holidays to facilitate participation and avoid the need for 
participants to take leave from work. 
- Transient vaccine viremia may occur following Qdenga vaccination. This condition has 
been reported in approximately 16% of individuals with prior dengue infection and 49% 
of those without previous dengue exposure. Symptoms typically begin during the 
second week after vaccination and last an average of four days. Reported symptoms 
Blood collection* 
 
X 
X 
 
X 
Randomization 
 
X 
 
 
 
Vaccination 
 
X 
X 
 
 
Adverse event check 
(also by google form+/-
telephone at 7, 30 day 
after each vaccination) 
 
X 
 
X 
X 

 
include headache, joint pain, myalgia, and rash. This event is less commonly observed 
after the second vaccine dose10 
- This study does not introduce additional risks beyond those associated with the 
standard use of the Qdenga vaccine, which is already approved for use in Thailand. 
Participants will be monitored and managed according to standard clinical practice. In 
the event of allergic reactions or other discomfort, investigators will provide appropriate 
medical care. 
- Blood collection may cause mild discomfort at the puncture site, minor bleeding, or 
bruising lasting 3–4 days. Infection at the puncture site is rare. Some individuals may 
experience dizziness or fainting, particularly those with needle or blood phobia. These 
risks will be minimized by having experienced nursing staff perform all blood draws. 
 
5.7.12 Data management and data analysis 
Data will be recorded in case record forms and subsequently entered into an electronic 
database using Microsoft Excel. Statistical analyses will be performed using the R software 
environment. 
Data analysis 
(1) Record and analyze data: using the R program version 3.5.1 
(2) Analysis data: 
- Continuous variables using Mean ± SD or Median (IQR) 
- Discrete variables using percentage 
- Compare qualitative variables data using Pearson's Chi-squared test or Fisher's exact test 
- Compare quantitative variables data using Student's t-test or Wilcoxon rank-sum test 
- A probability value (P) <0.05 was considered significant 
 
5.7.13 Study duration 
1 year, from 1 April 2025 to 30 September 2025. 
 
 
 
 

 
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