Yellow FeverPhase 2NCT01943305
The Role of Pre-existing Cross-reactive Antibodies in Determining the Efficacy of Vaccination in Humans
A Phase 2 study testing Japanese Encephalitis vaccine and Yellow Fever vaccine in people with Yellow Fever and Encephalitis, Japanese, run by Singapore General Hospital at 1 site in Singapore.
Trial summary
Epidemic viral diseases have become more prevalent in recent years. Among the various strategies to prevent such epidemics, vaccination is the most cost-effective. However, populations that are immunized are typically already exposed to multiple previous vaccinations or natural infections. Read more about this study
- Who is it for?
- Ages 21 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Yellow Fever, Encephalitis, Japanese
- What is being tested?
- Japanese Encephalitis vaccine and Yellow Fever vaccine
- Type of treatment
- Vaccines
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 84 participants
- Where
- 1 siteSingapore
- Study dates
- Oct 2013to Dec 2015
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy male or female adults, 21-50 years of age at the time of screening.
- Negative for anti-dengue antibodies by ELISA.
- Subjects who are willing to comply with the requirements of the study protocol and scheduled visits. (e.g., completion of the subject diary, return for follow-up visits) and who are willing to make themselves available for the duration of the study, with access to a consistent means of telephone contact, which may be either at home or at the workplace, land line, or mobile, but NOT a pay phone or other multiple-user device (i.e. a common-use phone serving multiple rooms or apartments).
- Subjects who give written informed consent approved by the Ethical Review Board governing the site.
- 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.
- Accessible vein the forearm for blood collection.
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- Females of non-child bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause.
- Female subjects of childbearing potential may be enrolled in the study
- if they have a negative urine pregnancy test on the day of screening and negative urine dipstick pregnancy tests at the days of the vaccinations
- if they use adequate, reliable contraception or abstain from sexual intercourse during the entire study for 1 year
Who cannot join
- Presence of acute infection in the preceding 7 days or presence of a temperature ≥ 38.0°C (oral temperature assessment), or acute symptoms greater than of "mild" severity on the scheduled date of first vaccination.
- History of severe drug and /or food allergies and/or known allergies to the trial product or its components.
- Any condition that, in the opinion of the investigator, would complicate or compromise the study or wellbeing of the subject.
- Woman who are pregnant or breast feeding.
- History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, neuropsychiatric, or immunosuppressive disorders that would be a risk factor when administered the IP.
- History of thymus gland disease.
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- Diagnosed with cancer or on treatment for cancer within the 3 years prior to the screening.
- Evidence of clinically significant anaemia and other any significant active haematological disease, or having donated > 450 mL of blood within the past three months.
- Evidence of substance abuse, or previous substance abuse.
- Participation in a study involving administration of an investigational compound within the past four months, or planned participation during the duration of this study.
- Administration of any licensed vaccine, such as MMR and/or Chickenpox immunisation within 30 days before the first study vaccine dose.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: An Open-label Phase 2a Clinical Trial to Test the Effect of Yellow Fever Vaccination in a Background of Japanese Encephalitis Antibodies.
Epidemic viral diseases have become more prevalent in recent years. Among the various strategies to prevent such epidemics, vaccination is the most cost-effective. However, populations that are immunized are typically already exposed to multiple previous vaccinations or natural infections. Studies from this and other laboratories have revealed that pre-existing dengue antibodies can either inhibit or enhance subsequent dengue infection depending on the pre-existing antibody levels. While cross-reactive antibody is potentially pathogenic in dengue, how it impacts immune response to vaccination is unclear. Indeed, aggregated at the site of vaccination and the respective draining lymph nodes are antigen-presenting and immune regulatory cells that express Fc receptors and play pivotal roles in determining the magnitude and polarity of the immune response. Vaccine uptake by these antigen-presenting cells may thus be either inhibited or enhanced when vaccines are opsonized with cross-reactive antibodies.
In view of the limited knowledge on how cross-reactive antibodies affect vaccination outcome, investigators propose here a study that exploits the known cross reactivity between Japanese encephalitis (JE) virus antibody and yellow fever (YF) vaccine. Investigators hypothesize that cross-reactive antibodies impacts antibody response to YF at the point vaccination in a concentration-dependent manner by altering both vaccine uptake and the innate immune response by antigen presenting cells. Investigators will structure an open label clinical trial on sequential vaccination with JE and YF vaccines, with different time intervals between vaccinations. This would test immune response to YF vaccination in subjects with different titer of cross-reactive JE vaccine-derived antibodies.
Read the detailed description
The primary objective of this clinical study is to examine the role of cross-reactive antibodies in modulating immune responses to vaccines.
- Hypothesis: Antibody response to YF vaccination is influenced by the heterologous antibody titer at the point of YF vaccination.
- Hypothesis : Heterologous antibody to YF affect magnitude of vaccine uptake through the Fc receptors and alters the quality and magnitude of the innate immune response following YF vaccination, which has been previously shown to predictive of immune response to YF vaccination.
Secondary objectives
- To determine neutralizing antibody response to YF vaccination in human volunteers at different time intervals following a prior JE vaccination.
- To characterize the innate immune response to YF vaccination at different time intervals after a prior JE vaccination.
A total of 100 healthy adults, pre-screened to be negative for anti-dengue antibodies will be enrolled upon written informed consent. 75 subjects in the test arm will received 2 doses of inactivated JE vaccine(Ixiaro), while 25 subjects in the control arm has no JE vaccination.
Subjects in the test arm will be sub-divided into 3 groups who receive YF17D:
Group1.YF vaccination 1-month post-JE vaccination Group 2.YF vaccination 4-months post-JE vaccination Group 3.YF vaccination 9-months post-JE vaccination Subjects in the control arm (group 4) will receive YF vaccination at the same time as group 1.
Blood sampling in relation to YF17D vaccination:
- Pre-dose
- 1-day after
- 3-days after (+ 1 day)
- 1-week after (± 2 days)
- 1-month after (± 5 days)
- 1-year after (± 14 days)
Primary end-point: Difference in geometric mean titre of YF17D neutralizing antibody.
- Conditions
- Yellow Fever, Encephalitis, Japanese
- Being tested
- Japanese Encephalitis vaccine, Yellow Fever vaccine
- Keywords
- Yellow Fever, vaccination, Japanese encephalitis, antibodies
- Medical subject headings
- Yellow Fever, Encephalitis, Japanese
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Japanese Encephalitis vaccineBiological
Also called Ixiaro
IXIARO, inactivated, adsorbed vaccine. Two doses (0.5 ml each) of IXIARO one month apart
Yellow Fever vaccineBiological
Also called Stamaril
STAMARIL, 1 dose (0.5 ml)
| Study group | Role | What they receive |
|---|---|---|
| Test arm | Experimental | A total of 100 healthy adults, pre-screened to be negative for anti-dengue antibodies will be enrolled upon written informed consent. 75 subjects in the test arm will received 2 doses of inactivated Japanese Encephalitis vaccine and 1 dose of Yellow Fever vaccine. Receives: Biological: Japanese Encephalitis vaccine; Biological: Yellow Fever vaccine |
| Control arm | Experimental | A total of 100 healthy adults, pre-screened to be negative for anti-dengue antibodies will be enrolled upon written informed consent. 25 subjects in the control arm will not receive Japanese Encephalitis vaccine but will receive 1 dose of Yellow Fever vaccine. Receives: Biological: Yellow Fever vaccine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Difference in geometric mean neutralizing antibody titer to YF17D as measured by plaque reduction neutralization test (PRNT) in volunteers receiving YF vaccination with or without prior JE vaccination
Measured: 1-month and 1-year post YF17D vaccine
Secondary outcomes (1)
Innate immune response to YF vaccination at different time intervals after a prior JE vaccination
Measured: transcriptional profiling of PBMC collected 1-day before, 1-, 3- and 7-days post YF17D vaccine
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Sep 2013 (estimated)
- Study startOct 2013
- Primary completionJun 2015
- Study completionDec 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Yellow FeverStudies of the same condition, open and under way.
- More trials run by Singapore General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 84 participants (actual)
Sponsor and investigators
- Lead sponsor
- Singapore General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Duke-NUS Graduate Medical School
- Responsible party
- Sponsor
- Investigators
- Jenny Low Guek Hong, Principal investigator, Singapore General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01943305
- Sponsor's protocol ID
- EID-JE/YF-01
- Status last verified
- Apr 2016
- First submitted
- 3 Sep 2013
- Last updated
- 20 Apr 2016
- Results posted
- No
- Data monitoring committee
- No
Publications
Low JG, Wijaya L, Li GK, Lim EY, Shum AK, Cheung YB, Ooi EE. The role of pre-existing cross-reactive antibodies in determining the efficacy of vaccination in humans: study protocol for a randomized controlled trial. Trials. 2015 Apr 10;16:147. doi: 10.1186/s13063-015-0651-z.
PubMed 25872531
Study at a glance
From the registry record, last updated by the sponsor on 20 Apr 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-label Phase 2a Clinical Trial to Test the Effect of Yellow Fever Vaccination in a Background of Japanese Encephalitis Antibodies.
- ClinicalTrials.gov ID
- NCT01943305
- Acronym / sponsor ID
- EID-JE/YF-01
- Conditions
- Yellow Fever, Encephalitis, Japanese
- Keywords
- Yellow Fever, vaccination, Japanese encephalitis, antibodies
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 84 participants (actual)
- Lead sponsor
- Singapore General HospitalUniversity, hospital or other
- Collaborators
- Duke-NUS Graduate Medical School
- Study start
- Oct 2013
- Primary completion
- Jun 2015 (actual)
- Study completion
- Dec 2015 (actual)
- First posted
- 16 Sep 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Epidemic viral diseases have become more prevalent in recent years. Among the various strategies to prevent such epidemics, vaccination is the most cost-effective. However, populations that are immunized are typically already exposed to multiple previous vaccinations or natural infections. Studies from this and other laboratories have revealed that pre-existing dengue antibodies can either inhibit or enhance subsequent dengue infection depending on the pre-existing antibody levels. While cross-reactive antibody is potentially pathogenic in dengue, how it impacts immune response to vaccination is unclear. Indeed, aggregated at the site of vaccination and the respective draining lymph nodes are antigen-presenting and immune regulatory cells that express Fc receptors and play pivotal roles in determining the magnitude and polarity of the immune response. Vaccine uptake by these antigen-presenting cells may thus be either inhibited or enhanced when vaccines are opsonized with cross-reactive antibodies.
In view of the limited knowledge on how cross-reactive antibodies affect vaccination outcome, investigators propose here a study that exploits the known cross reactivity between Japanese encephalitis (JE) virus antibody and yellow fever (YF) vaccine. Investigators hypothesize that cross-reactive antibodies impacts antibody response to YF at the point vaccination in a concentration-dependent manner by altering both vaccine uptake and the innate immune response by antigen presenting cells. Investigators will structure an open label clinical trial on sequential vaccination with JE and YF vaccines, with different time intervals between vaccinations. This would test immune response to YF vaccination in subjects with different titer of cross-reactive JE vaccine-derived antibodies.
Detailed description
The primary objective of this clinical study is to examine the role of cross-reactive antibodies in modulating immune responses to vaccines.
- Hypothesis: Antibody response to YF vaccination is influenced by the heterologous antibody titer at the point of YF vaccination.
- Hypothesis : Heterologous antibody to YF affect magnitude of vaccine uptake through the Fc receptors and alters the quality and magnitude of the innate immune response following YF vaccination, which has been previously shown to predictive of immune response to YF vaccination.
Secondary objectives
- To determine neutralizing antibody response to YF vaccination in human volunteers at different time intervals following a prior JE vaccination.
- To characterize the innate immune response to YF vaccination at different time intervals after a prior JE vaccination.
A total of 100 healthy adults, pre-screened to be negative for anti-dengue antibodies will be enrolled upon written informed consent. 75 subjects in the test arm will received 2 doses of inactivated JE vaccine(Ixiaro), while 25 subjects in the control arm has no JE vaccination.
Subjects in the test arm will be sub-divided into 3 groups who receive YF17D:
Group1.YF vaccination 1-month post-JE vaccination Group 2.YF vaccination 4-months post-JE vaccination Group 3.YF vaccination 9-months post-JE vaccination Subjects in the control arm (group 4) will receive YF vaccination at the same time as group 1.
Blood sampling in relation to YF17D vaccination:
- Pre-dose
- 1-day after
- 3-days after (+ 1 day)
- 1-week after (± 2 days)
- 1-month after (± 5 days)
- 1-year after (± 14 days)
Primary end-point: Difference in geometric mean titre of YF17D neutralizing antibody.
Study design
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Test arm | Experimental | Biological: Japanese Encephalitis vaccine, Biological: Yellow Fever vaccineA total of 100 healthy adults, pre-screened to be negative for anti-dengue antibodies will be enrolled upon written informed consent. 75 subjects in the test arm will received 2 doses of inactivated Japanese Encephalitis vaccine and 1 dose of Yellow Fever vaccine. |
| Control arm | Experimental | Biological: Yellow Fever vaccineA total of 100 healthy adults, pre-screened to be negative for anti-dengue antibodies will be enrolled upon written informed consent. 25 subjects in the control arm will not receive Japanese Encephalitis vaccine but will receive 1 dose of Yellow Fever vaccine. |
Who may qualify
- Ages
- 21 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (10 listed)
- Healthy male or female adults, 21-50 years of age at the time of screening.
- Negative for anti-dengue antibodies by ELISA.
- Subjects who are willing to comply with the requirements of the study protocol and scheduled visits. (e.g., completion of the subject diary, return for follow-up visits) and who are willing to make themselves available for the duration of the study, with access to a consistent means of telephone contact, which may be either at home or at the workplace, land line, or mobile, but NOT a pay phone or other multiple-user device (i.e. a common-use phone serving multiple rooms or apartments).
- Subjects who give written informed consent approved by the Ethical Review Board governing the site.
- 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.
Key exclusion criteria (11 listed)
- Presence of acute infection in the preceding 7 days or presence of a temperature ≥ 38.0°C (oral temperature assessment), or acute symptoms greater than of "mild" severity on the scheduled date of first vaccination.
- History of severe drug and /or food allergies and/or known allergies to the trial product or its components.
- Any condition that, in the opinion of the investigator, would complicate or compromise the study or wellbeing of the subject.
- Woman who are pregnant or breast feeding.
- History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, neuropsychiatric, or immunosuppressive disorders that would be a risk factor when administered the IP.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Japanese Encephalitis vaccineAlso: IxiaroIXIARO, inactivated, adsorbed vaccine. Two doses (0.5 ml each) of IXIARO one month apart | Biological | Test arm |
| Yellow Fever vaccineAlso: StamarilSTAMARIL, 1 dose (0.5 ml) | Biological | Control arm, Test arm |
Primary outcome
Difference in geometric mean neutralizing antibody titer to YF17D as measured by plaque reduction neutralization test (PRNT) in volunteers receiving YF vaccination with or without prior JE vaccination
Time frame: 1-month and 1-year post YF17D vaccine
1 secondary outcome
Innate immune response to YF vaccination at different time intervals after a prior JE vaccination
Time frame: transcriptional profiling of PBMC collected 1-day before, 1-, 3- and 7-days post YF17D vaccine
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Apr 2016.
- Derived from this study: PubMed 25872531Low JG, Wijaya L, Li GK, Lim EY, Shum AK, Cheung YB, Ooi EE. The role of pre-existing cross-reactive antibodies in determining the efficacy of vaccination in humans: study protocol for a randomized controlled trial. Trials. 2015 Apr 10;16:147. doi: 10.1186/s13063-015-0651-z.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jenny Low Guek Hong principal investigator
Singapore General Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Japanese Encephalitis vaccine and Yellow Fever vaccine in people with Yellow Fever and Encephalitis, Japanese, run by Singapore General Hospital at 1 site in Singapore.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Apr 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Difference in geometric mean neutralizing antibody titer to YF17D as measured by plaque reduction neutralization test (PRNT) in volunteers receiving YF vaccination with or without prior JE vaccination (time frame: 1-month and 1-year post YF17D vaccine). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01943305, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Apr 2016.