We hypothesize that a high CD4+ and CD8+ T cell count will reduce viremia upon challenge with a structurally heterologous virus, and correspondingly result in reduced magnitude of host response to challenge infection.

Primary Objective: To compare, after challenge with a structurally heterologous vaccine, the differences in levels of viremia between healthy adults who received primary vaccination with either YF17D vaccine, chimeric JE-YF17D vaccine, or inactivated JE vaccine.

58 subjects will be randomised into 1 of 2 arms (Arm B1 and Arm B2) in a 1:1 ratio, in a double-blind fashion. Subjects in Arm B1 will receive JE-YF17D vaccine (Imojev, Sanofi Pasteur) on Day 0 followed by YF17D vaccine (Stamaril, Sanofi Pasteur) on Day 28. Subjects in Arm B2 will receive Stamaril on Day 0 followed by Imojev on Day 28. Arm B3 will be conducted as a separate single-arm open label design in 14 subjects. Subjects in Arm B3 will receive inactivated JE vaccine (Ixiaro, Valneva) on Day 0 followed by Stamaril on Day 28.

The rationale for these three study arms is as follows: Arm B1 will show the impact low levels of viremia, and the resultant low levels of virus-specific CD4+ and CD8+ T cells, would have on YF17D infection. In contrast, YF17D vaccination in Arm B2 would produce high levels of viremia, and in turn high levels virus-specific T cells, thus likely ameliorating JE-YF17D infection. Arm B3 will serve as the control arm, as vaccination with inactivated JE vaccine would not produce any YF17D-specific T cell response. Notably, the first vaccination in Arms B1 and B2 would also provide the viremia response in the absence of virus-specific T cells, which would serve as a reference point to interpret the outcome of the second vaccination.

Criteria for Recruitment and Recruitment Process: Subjects will be recruited from SingHealth Investigational Medicine Unit (IMU) healthy volunteer database and recruitment posters. Subjects will be given a copy of the Participant Information and Informed Consent Form to read upon their arrival. A briefing session on the study will be conducted by the Investigator. Thereafter, subjects will be ushered into a private room where informed consent is obtained and where questions about the study can be asked freely. Subjects will not be rushed into making a decision to participate in the study. They will be encouraged to speak to their family members about participation in the study; and allowed to defer their decision (without any prejudice) to participate till after discussion with their family members.

Screening Visits and Procedures: Subjects will be recruited via the SingHealth Investigational Medicine Unit (IMU). Informed written consent will be sought from subjects who fulfill criteria for enrollment. All consented subjects will undergo screening, which includes physical examination, full blood count, liver function test, anti-dengue antibodies ELISA (Enzyme-Linked Immunosorbent Assay) and urinary pregnancy test (for female subjects of child-bearing potential).

A urine pregnancy test will be performed at screening and on the day of vaccination (day 0 and day 28) for female subjects of child-bearing potential. Only those with a negative urine pregnancy test will be considered to be eligible for the study, provided that other eligibility criteria were fulfilled.

Both male (if he has a partner of childbearing potential) and female subjects (of childbearing potential) must agree to use adequate and reliable contraceptive measures (e.g. spermicides, condoms, contraceptive pills) or practice abstinence for 10 days after vaccination.

Study Visits and Procedures: 58 subjects will be randomised into 1 of 2 arms (Arm B1 and Arm B2) in a 1:1 ratio, in a double-blind fashion. Subjects in Arm B1 will receive JE-YF17D vaccine (Imojev, Sanofi Pasteur) on Day 0 followed by YF17D vaccine (Stamaril, Sanofi Pasteur) on Day 28. Subjects in Arm B2 will receive Stamaril on Day 0 followed by Imojev on Day 28. Arm B3 will be conducted as a separate single-arm open label design in 14 subjects. Subjects in Arm B3 will receive inactivated JE vaccine (Ixiaro, Valneva) on Day 0 followed by Stamaril on Day 28. Study visits in all arms will occur on Day 0, 4, 7, 10, 14, 28, 29, 32, 35, 38, 42, 58. At each study visit, physical examination, vital signs and research blood sampling will be performed. On Day 0 and Day 28, blood sampling will be performed prior to vaccination.

Final study visit: Last study visit will be on Day 58 post-study vaccination.

Post study follow up and procedures: There is no requirement for post-study follow-up or procedures.

Safety Monitoring Plan: The study may be evaluated by government inspectors/ regulatory authorities who must be allowed access to e-CRFs, source documents, and other study files. The inspectors will review CRFs and compare them with source documents to verify accurate and complete collection of data and confirm that the study is being conducted according to the protocol, ICH Good Clinical Practices (ICH-GCP) and all applicable regulations.

At any time post-vaccination, all subjects will be trained to observe for systemic AEs. A diary will also be given to the subjects to record such events should they occur during this period. Should they develop systemic symptoms that require intervention, they will report to the study site for medical evaluation and receive the appropriate therapy. Duration of symptoms will be recorded. Any concomitant medication use during this period will also be recorded.

During the study, full history taking and physical examination will be performed at both scheduled and unscheduled visits. A full physical examination will only be done at the screening visit, while a brief physical examination will be done for all subsequent visits. The Common Terminology Criteria for Adverse Events (CTCAE), routinely employed in clinical trials, will be used to define AE terminology and severity. Management of AEs is at the discretion of the study team PI and co-Is, guided by severity and clinical indication for intervention. All medication prescribed for the management of AEs will be documented in the medication/concomitant medication clinical record form. Details of AE event terminology, date and time of event start and end, severity, using the CTCAE or treatment given, impact on work and to the continuation of the study, and final outcome of the event will be recorded on the case report until resolution of the event.

Data Quality Assurance: The PI and Co-Is will review the study periodically for data and safety monitoring. Internal quality checks will be performed by two CRCs who are study team members. The data entered by one CRC will be checked by another using the source documents. The study may also be picked for monitoring by SingHealth Office of Research Integrity and Compliance (ORIC) or evaluated by government inspectors/regulatory authorities who must be allowed access to e-CRFs, source documents, and other study files. The monitors/inspectors may review CRFs and compare them with source documents to verify accurate and complete collection of data and confirm that the study is being conducted according to the protocol, ICH-Good Clinical Practices (ICH-GCP) and all applicable regulations.

Data Entry and Storage: All participant's data will be de-identified upon recruitment. Hardcopy research data collection forms such as CRFs, logs and diaries will be kept in the Investigator's Site File and stored in SingHealth IMU under lock and key, accessible only to delegated study team members.

Direct data capture of demographic and clinical data will be captured on source documents. Identifiers will be kept in a separate file in another office and every effort will be made to protect the privacy of the participants. The data to be analysed will contain only de-identified data. An electronic data capture system will be used. All electronic data will be password protected and can only be accessed by study team members. Specimens, test results or pathogen data will be stored at Duke-NUS EID laboratory in a stand-alone PC whereby access is password protected.

Determination of sample size: To detect an effect size of 0.8 SD in mean viremia level on log(10) scale between first and second with the same vaccine - first dose of will be analysed against those who received YF17D after JE-YF17D and vice versa - a sample size of 25 per group will provide 80% power at 5% two-sided type 1 error rate. To allow for 10% early dropouts, a total sample size of 28 per group for Arm B1 and B2 is targeted. For Arm B3, which is the control group, a sample size of 14 will be used.

Statistical and Analytical plan: Distributional diagnostic plots will be used to examine the shape of distributions of T-cell counts immediately before the challenge vaccination and the subsequent vaccine viremia. Parametric (t-test) or non-parametric (Mann-Whitney U) procedures will be used to assess the differences in T-cell counts and the various measured variables such as viremia, antibody titres and cytokine levels. Pearson's or Spearman's correlation coefficients will be used, as appropriate, to examine the association between T-cell levels and these variables.

The frequency of symptoms reported and the type of symptoms will first be analysed by determining the median and the interquartile ranges. We will then analyse how the first vaccination impact the symptomatic outcome of the challenge vaccination using 2x2 tables and chi square analysis or Fisher's exact test, whichever is appropriate. Parametric (t-test) or non-parametric (Mann-Whitney U) procedures will be used to assess the differences in pre-challenge virus-specific T-cell counts among those with symptoms and those without.

Tests which will be performed on the blood samples: DENV IgG ELISA, FBC, Liver Panel, Viremia (NS5 PCR), cytokines, Anti-NS1 Ab, T-cell studies (AIM, ELLISPOT, ELLA), BCR sequencing, PRNT and gene expression.

Inclusion Criteria:

1. Healthy adults, 21-45 years of age at time of screening
2. Willing to comply to study procedures and adhere to study schedule visits.
3. Satisfactory baseline medical assessment as assessed by physical examination and a stable health status. The laboratory values must be within the normal range of the assessing site or show abnormalities that are deemed not clinically significant as judged by the investigator. A stable health status is defined as the absence of a health event satisfying the definition of a serious adverse event.
4. Accessible vein for blood collection.
5. Ability to provide informed consent.
6. Female subjects of non-child bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause. Post-menopausal subjects must have had at least 12 months of natural (spontaneous) amenorrhea
7. Female subjects of child bearing potential with negative urine pregnancy tests on the day of screening and vaccination.
8. Both male (if he has a partner of childbearing potential) and female subjects (of childbearing potential) must agree to use adequate and reliable contraceptive measures (e.g. spermicides, condoms, contraceptive pills) or practice abstinence for 10 days after vaccination.

Exclusion Criteria:

1. History of presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, neuropsychiatric, haematological, endocrine or immunosuppressive disorders that would be a risk factor when administered the investigational product (IP)
2. Previous receipt of Imojev, Stamaril or Ixiaro vaccines, or any other yellow fever or Japanese encephalitis vaccines
3. Previous history of Yellow fever virus or Japanese encephalitis infection
4. Known allergy to Imojev, Stamaril or Ixiaro vaccines or their components
5. History of severe food/drug/vaccine allergies e.g. angioedema, anaphylaxis
6. Known allergy to egg or egg products
7. History of thymus gland disease
8. Diagnosed with cancer or on treatment for cancer (with the exception of localized basal cell carcinoma) within 3 years prior to screening
9. Evidence of clinically significant anemia (Hb <10 g/dl)
10. Blood donation exceeding >450mls in the past 3 months
11. Presence of acute infection in the preceding 7 days or presence of a temperature ≥ 38.0°C (oral or tympanic temperature assessment), or acute symptoms greater than of "mild" severity on the scheduled date of first dose
12. Woman who is pregnant or breast feeding
13. Evidence of substance abuse, or previous substance abuse including alcohol
14. Participation in a study involving administration of an investigational compound (including investigational vaccines) within the past three months, or planned participation during the duration of this study.
15. Receipt of anti-inflammatory drugs (such as NSAIDs or systemic steroids) in the past 7 days.
16. Receipt of any licensed vaccine in the past 30 days before the first study vaccine dose.
17. Positive serum Dengue IgG by ELISA
18. Any condition that, in the opinion of the investigator, would complicate or compromise the study or wellbeing of the subject.

Arms B1 and B2 will be double-blinded. Arm B3 will be open label.