Non- Inferiority Fractional-doses Trial for Yellow Fever Vaccine

NCT04059471 | Completed Phase 4 DMC

• 5 other identifiers: OxTREC Ref: 2-19SERU 3797HS 2596MUREC 1/7ECCT/19/03/04
• Study Type: interventional
• Target: 900
• Locations: 2 countries
• Sites: 2

Brief Summary

In the recent past there has been a number of large urban Yellow Fever outbreaks in sub-Saharan Africa, tropical South Americas, The demand for Yellow Fever vaccines in response to the large urban outbreaks occurring concurrently and the risk of further spread through Africa and to Asia was larger than the available global supply. In this situation, the World Health Organisation (WHO) developed recommendations for the use of fractional doses of Yellow Fever vaccine as a dose-sparing strategy. These recommendations were based on data from a limited number of clinical trials, none of which had been conducted in Africa. This was due to the uncertainties on the minimum dose requirement. Our study complements a study which is comparing full standard dose to 1/5th of standard dose of all four WHO-prequalified YF vaccines in adults (ClinicalTrials.gov number: NCT02991495), and is currently ongoing at KEMRI CGMRC and Epicentre, Mbarara which is designed to answer questions on the use of current stock of YF vaccines with a potency as close as possible to each manufacturers' minimum release. Data from this trial will inform a WHO recommendation on using 1/5th of the current standard dose of vaccine for outbreak control. However, since many vials will contain excess YF vaccine such that 1/5th of a vial is likely to be substantially above the current minimum potency requirements, these data may not be scientifically explanatory regarding the minimum dose required for preventive use. The new complementary study, aims to determine the lowest YF vaccine dose that is non-inferior to the current standard full dose among populations in sub-Saharan Africa. The study will be conducted in Kenya (KEMRI Center for Geographical Medicine Research-Coast (CGMR-C), Kilifi) and Uganda (Epicentre, Mbarara) with trial participants recruited at both sites, using vaccine from one WHO-prequalified manufacturer (Institut Pasteur de Dakar, Senegal (IPD)).

Conditions

Yellow Fever

Keywords

Yellow Fever vaccine; Fractional doses; Yellow Fever; Vaccine dose

Outcome Measures

Primary Outcomes (1)

• The proportion of vaccinees that seroconverts as measured by Plaque Reduction Neutralisation Test (PRNT-50)

  PRNT-50 will be used to quantify functional antibodies by neutralisation of the virus

  28 days post vaccination

Secondary Outcomes (7)

• Duration of immunity as measured by PRNT

  10 days, 28 days, 1 year and 2 years (adults)

• Change in the geometric mean fold of the antibody titre as measured by PRNT

  Baseline and 28 days after vaccination

• Other flavivirus antibodies interference as tested by neutralisation tests

  Baseline and 28 days after vaccination

• Post-vaccination viremia as measured by quantitative Polymerase Chain Reaction (PCR)

  baseline, and on days 2, 3, 4, 5, 6, 7 and 10 after vaccination

• Changes in cellular immunology

  baseline and days 10 and 28 post-vaccination.

Study Arms (4)

Standard Dose

ACTIVE COMPARATOR

Yellow fever vaccine, Institut Pasteur, standard dose as release by manufacturer will be administered subcutaneously once.

Biological: Yellow fever vaccine, Institut Pasteur

Fractional dose (1000 IU/dose)

EXPERIMENTAL

Yellow fever vaccine, Institut Pasteur, will be titrated to about 1000IU/dose and administered subcutaneously once.

Biological: Yellow fever vaccine, Institut Pasteur

Fractional dose (500 IU/dose)

EXPERIMENTAL

Yellow fever vaccine, Institut Pasteur, will be titrated to about 500IU/dose and administered once.

Biological: Yellow fever vaccine, Institut Pasteur

Fractional dose (250 IU/dose)

EXPERIMENTAL

Yellow fever vaccine, Institut Pasteur, will be titrated to about 250IU/dose and administered once.

Biological: Yellow fever vaccine, Institut Pasteur

Interventions

Yellow fever vaccine, Institut Pasteur BIOLOGICAL

Full dose and 500IU/dose

Also known as: Children sub-study

Fractional dose (1000 IU/dose); Fractional dose (250 IU/dose); Fractional dose (500 IU/dose); Standard Dose

Eligibility Criteria

• Age: 9 Months - 59 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Individuals aged ≥18 - \<60 years of age.
• Children aged between 9 months and 12 months.
• HIV negative on serological screening OR HIV positive adults and children aged \> 18 months on serological testing, and no symptoms suggestive of current clinical immunosuppression and cluster of differentiation-4 (CD4) count\>200 (for adults) and CD4% \> 25% (for children aged 9-12 months) within the last 6 months.
• Ability to provide informed consent to participate in the study

You may not qualify if:

• Known contraindications to YF vaccination such as allergies to egg protein and chicken products or any component of the vaccine (including gelatin, eggs, eggs products or chicken products), immunodeficiency, known thymus disorder, such as thymoma and myasthenia gravis
• Using corticosteroids or other immunosuppressive therapy
• Thymus disorder, such as thymoma and myasthenia gravis
• Acute febrile disease on the day of vaccination with temperature \>37.5 degrees Celsius is a temporal contraindication.
• Previous YF vaccination
• Previous YF infection as determined from history
• Pregnancy (as determined by a urine test on the proposed day of vaccination) and lactating women
• Planning to migrate out of the study areas before the end of the study follow-up
• Planning to travel to a country requiring YF vaccination certificate within the first year after vaccination.
• Any condition or criteria, including acute or chronic clinically significant abnormality that in the opinion of the investigator might compromise the wellbeing of the volunteer or interfere with the outcome of the study.

Sponsors & Collaborators

• University of Oxford: lead
• KEMRI-Wellcome Trust Collaborative Research Program: collaborator
• Institut Pasteur: collaborator
• MRC/UVRI and LSHTM Uganda Research Unit: collaborator
• Epicentre, Paris, France.: collaborator

Study Sites (2)

KEMRI-Wellcome Trust Research Programme

Kilifi, Coast, 254, Kenya

Location

Epicentre, Mbarara.

Mbarara, Uganda

Location

Related Publications (3)

• Kimathi D, Juan-Giner A, Bob NS, Orindi B, Namulwana ML, Diatta A, Cheruiyot S, Fall G, Dia M, Hamaluba MM, Nyehangane D, Karanja HK, Gitonga JN, Mugo D, Omuoyo DO, Hussein M, Oloo E, Kamau N, Wafula J, Bendera J, Silvester N, Mwavita J, Joshua M, Thuranira JM, Agababyona C, Ngetsa C, Aisha N, Moki F, Buluku T, Munene M, Mwanga-Amumpaire J, Lutwama J, Kayiwa J, Kamaara E, Barrett AD, Kaleebu P, Bejon P, Sall AA, Grais RF, Warimwe GM. Low-dose yellow fever vaccination in infants: a randomised, double-blind, non-inferiority trial. Lancet. 2026 Jan 13:S0140-6736(25)02069-0. doi: 10.1016/S0140-6736(25)02069-0. Online ahead of print.

  PMID: 41544642 DERIVED

• Kimathi D, Juan-Giner A, Bob NS, Orindi B, Namulwana ML, Diatta A, Cheruiyot S, Fall G, Dia M, Hamaluba MM, Nyehangane D, Karanja HK, Gitonga JN, Mugo D, Omuoyo DO, Hussein M, Oloo E, Kamau N, Wafula J, Bendera J, Silvester N, Mwavita J, Joshua M, Mwendwa J, Agababyona C, Ngetsa C, Aisha N, Moki F, Buluku T, Munene M, Mwanga-Amumpaire J, Lutwama J, Kayiwa J, Kamaara E, Barrett AD, Kaleebu P, Bejon P, Sall AA, Grais RF, Warimwe GM; NIFTY Investigators. Low-Dose Yellow Fever Vaccine in Adults in Africa. N Engl J Med. 2025 Feb 20;392(8):788-797. doi: 10.1056/NEJMoa2407293.

  PMID: 39970397 DERIVED

• Kimathi D, Juan A, Bejon P, Grais RF, Warimwe GM; YEFE and NIFTY vaccine trials teams. Randomized, double-blinded, controlled non-inferiority trials evaluating the immunogenicity and safety of fractional doses of Yellow Fever vaccines in Kenya and Uganda. Wellcome Open Res. 2019 Nov 20;4:182. doi: 10.12688/wellcomeopenres.15579.1. eCollection 2019.

  PMID: 31984244 DERIVED

MeSH Terms

Conditions

Yellow Fever

Interventions

Yellow Fever Vaccine

Condition Hierarchy (Ancestors)

Mosquito-Borne Diseases; Vector Borne Diseases; Infections; Arbovirus Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Hemorrhagic Fevers, Viral

Intervention Hierarchy (Ancestors)

Viral Vaccines; Vaccines; Biological Products; Complex Mixtures

Study Officials

• Philip Bejon, PhD

  University of Oxford

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Investigators and participants will be blinded to the allocations. Only the pharmacist and the nurse administering the vaccine will be unblinded. The allocation will be to one of the four treatment arms per a computer-generated randomization schedule. Allocations will be concealed until a member of the unblinded study team scratches the randomization booklet to reveal the participants' randomization arm.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Adult participants (n=480) will be randomized for vaccination with full standard dose or with 1000, 500 or 250 IU (i.e. 4 arms) with a 1:1:1:1 allocation ratio. Results for the safety and primary outcome of the adult study will then be reviewed by the DSMB, and the lowest non-inferior dose in the adult study selected for assessment in children aged 9 months to 5 years (n=420) in comparison to full standard dose (i.e. 2 arms) with a 1:1 allocation ratio.

Study Record Dates

• First Submitted: July 26, 2019
• First Posted: August 16, 2019
• Study Start: November 11, 2019
• Primary Completion: March 30, 2020
• Study Completion: June 24, 2023
• Last Updated: February 9, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

KE (1); UG (1)