Flavivirus Cross-priming Potential of IMOJEV (FlaviPrime)

Flavivirus Cross-priming Potential of Live Attenuated Japanese Encephalitis (JE) Vaccine IMOJEV in Flavivirus naïve and Flavivirus Experienced Participants

There is a pressing need for a better experimental system to understand flavivirus antibody responses, beyond dengue, to make sure the investigators are using current vaccines to greatest effect and to inform the development of next-generation vaccines. This study will use live chimeric JE vaccine IMOJEV® as a tool for flavivirus epitope discovery. This will allow experimental JEV infection using replication competent, live, attenuated virus as a model, in a setting where the flavivirus infection history of humans can be tightly controlled.

Study Overview

• Status: Completed
• Conditions: Japanese Encephalitis
• Intervention / Treatment: Biological: IMOJEV

Detailed Description

This study will test the hypothesis that in previously flavivirus-exposed individuals, the antibody response is more broadly cross neutralising, and that this will lead to the identification of conserved virion surface epitopes that could be the target of second generation vaccines.

Exploratory Primary Objectives/Specific aims:

1. To establish a human model system of JEV infection in healthy adult volunteers using live attenuated JE vaccine IMOJEV®.
2. To sort and sequence individual responding B cells (plasmablasts) after vaccination with IMOJEV®, and to generate human monoclonal antibodies to JEV.
3. To generate JEV specific human monoclonal antibodies from the sequences derived in (2).
4. To describe the development, specificity, cross-reactivity and function of the T cell response to IMOJEV®.
5. To establish a sample bank for future work on cross-reactive and other responses to flaviviruses, flavivirus vaccines and other emergent viruses.

Exploratory Secondary Objectives:

1. To examine the specificity and cross-reactivity of the antibody response after JE vaccination, using serum and human monoclonal antibodies.
2. To determine whether there are epitopes which can serve as the target of broadly cross-neutralising antibody responses.

Experimentally the fine specificity and cross-reactivity of the antibody response will be studied by cloning antibodies from plasmablasts (B cells responding to the vaccine) that have been single cell sorted by flow cytometry then sequenced at one week post vaccine. These human monoclonal antibodies will then be mapped on to the surface of the virus particle using established approaches, and tested to look for cross-reactive antibodies. T cell responses to the vaccine will be studied using custom pools of synthetic peptides by ELISpot and flow cytometry.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Liverpool, United Kingdom, L7 8XP
    • Liverpool University Hospitals NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. A male or female adult between 18 and 70 years of age at consent.
2. Written and informed consent obtained from participant and agreement of participant to comply with the requirements of the study
3. Able to attend regularly to donate study blood samples for the duration of the study (8 weeks), no planned re-location or travel to a flavivirus endemic area during the study period.
4. Satisfactory medical screen, as demonstrated by study screening document normal physical examination and normal screening blood tests
5. Group 1: Any flavivirus exposure status; Group 2: No previous flavivirus vaccination (JE, tick borne encephalitis or yellow fever (YF)), no residence in a flavivirus endemic area nor planned travel to a flavivirus endemic area during the period of the study; Group 3: JE vaccine and/or yellow fever vaccine or other proven flavivirus infection within the last 10 years or other proven flavivirus infection (lifetime).
6. An efficacious method of contraception must be used during the study for women of childbearing potential.

Exclusion Criteria:

1. Use of any investigational or non-registered drug within 5 half-lives of the drug, or 30 days preceding administration of study JE vaccine, whichever is longer; or planned use during the study period.
2. Receipt of any investigational biologic agents with mechanisms of action that might affect the immune system, at the discretion of the CI and local PI.
3. Administration of immunosuppressants or other immune-modifying drugs within a period of six months before vaccination or at any time during the study period; participants who have received these agents may also be excluded at the discretion of the CI and local PI.
4. Any confirmed or suspected immunosuppressive or immunodeficient condition.
5. A family history of congenital or hereditary immunodeficiency.
6. Any antiviral drug therapy within a period of 5 drug half-lives or 30 days before vaccination, whichever is longer, or at any time during the study period.
7. History of significant allergic reactions likely to be exacerbated by any component of the study vaccine, especially allergic disease or reactions to any previous dose of any vaccine.
8. History of having received JE vaccine, yellow fever vaccine, tick-borne encephalitis vaccine or experimental flavivirus vaccine (group 2 only).
9. Detectable anti Flavivirus neutralizing antibodies in screening tests (group 2 only).
10. Acute disease (for example acute infection) at the time of enrolment or vaccination, if symptoms are rated as anything more significant than a mild adverse event. Entry into the study and/or vaccination may be deferred until the illness has resolved for at least one week.
11. Acute or chronic, clinically significant in the opinion of the investigator, disease in any organ system, as determined by history, physical examination or laboratory testing.
12. Presence of any inflammatory condition that might require immunomodulatory therapy.
13. Recent blood donation (inclusion can be delayed under these circumstances; the participant should be enrolled 16 weeks after their last blood donation. Each participant should give no more than 470 ml per 16 weeks, so regular blood donation should be suspended during the study and can re-commence 1 month after the last study sample).
14. Current or previous abattoir worker or sheep farmer in Scotland (risk of Louping ill virus exposure; group 2 only).
15. Administration of immunoglobulins and/or any blood products within the three months preceding administration of vaccine, or planned administration during the study period.
16. Seropositive for HIV.
17. Pregnancy or Lactation.
18. History of excessive alcohol consumption (>28 units per week), drug abuse or significant psychiatric illness.
19. Any other condition or consideration that, in the opinion of the Investigator, would pose a health risk to the participant if they were enrolled in the study, or would otherwise interfere with the evaluation of the study aims (e.g. difficult venesection).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Group 1 - Any status; Up to 3-4 healthy adults	Biological: IMOJEV; live attenuated Japanese encephalitis (JE) vaccine IMOJEV®
Other: Group 2 - FlaviPrime Naive; Up to 6-8 healthy adults who have never travelled to a flavivirus endemic area and are negative in screening tests for flavivirus immunity.	Biological: IMOJEV; live attenuated Japanese encephalitis (JE) vaccine IMOJEV®
Other: Group 3 - Flavivirus Exposed; Up to 8-10 healthy adults who have had JE vaccine and/or are previously flavivirus exposed, either through receiving yellow fever vaccine up to 5 years before the study, or from being diagnosed with a flavivirus illness (e.g. dengue or Zika).	Biological: IMOJEV; live attenuated Japanese encephalitis (JE) vaccine IMOJEV®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary: Plasmablast percentage of total B cells at 7 days post vaccine	Plasmablast percentage of total B cells at 7 days post vaccine Number of plasmablasts sorted by flow cytometry at 7 days post vaccine	1 week
Primary: Neutralising antibody titre, measured by 50% of viral plaque reduction at one and two months post vaccine	Neutralising antibody titre, measured by 50% of viral plaque reduction at one and two months post vaccine	two months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary: Number of adverse events occurring in all participants in one month post vaccine	Number of adverse events occurring in all participants in one month post vaccine	one month

Collaborators and Investigators

• Sponsor: University of Liverpool
• Investigators: Principal Investigator: Lance Turtle, Dr, University of Liverpool

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2021
• Primary Completion (Actual): December 23, 2021
• Study Completion (Actual): May 11, 2022

Study Registration Dates

• First Submitted: April 4, 2019
• First Submitted That Met QC Criteria: April 17, 2019
• First Posted (Actual): April 18, 2019

Study Record Updates

• Last Update Posted (Actual): November 1, 2022
• Last Update Submitted That Met QC Criteria: October 31, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; RNA Virus Infections; Virus Diseases; Infections; Encephalitis, Arbovirus; Encephalitis, Viral; Central Nervous System Viral Diseases; Central Nervous System Infections; Infectious Encephalitis; Arbovirus Infections; Vector Borne Diseases; Flavivirus Infections; Flaviviridae Infections; Encephalitis, Japanese; Encephalitis
• Other Study ID Numbers: UoL001462 - 4833

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No