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Immunogenicity and Safety of Fractional Doses of Yellow Fever Vaccines (YEFE) (YEFE)

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ClinicalTrials.gov Identifier: NCT02991495
Recruitment Status : Recruiting
First Posted : December 13, 2016
Last Update Posted : August 14, 2019
Sponsor:
Collaborator:
Kenya Medical Research Institute
Information provided by (Responsible Party):
Epicentre

Tracking Information
First Submitted Date  ICMJE December 7, 2016
First Posted Date  ICMJE December 13, 2016
Last Update Posted Date August 14, 2019
Actual Study Start Date  ICMJE November 6, 2017
Actual Primary Completion Date February 21, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 27, 2017)
Seroconversion by PRNT50 (Plaque Reduction Neutralization Test 50 value) [ Time Frame: 28 days post-vaccination ]
Plaque reduction neutralization test will be used to quantify the titer of neutralising antibody for the virus
Original Primary Outcome Measures  ICMJE
 (submitted: December 12, 2016)
Seroconversion by PRNT50 [ Time Frame: 28 days post-vaccination ]
Change History Complete list of historical versions of study NCT02991495 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 27, 2018)
  • Assessment of protection by PRNT50 (Plaque Reduction Neutralization Test 50 value) [ Time Frame: 10 days post-vaccination ]
    Plaque reduction neutralization test will be used to quantify the titer of neutralising antibody for the virus
  • Duration of immunity [ Time Frame: 1 year post-vaccination ]
    Assessment of duration of immunity at 1 year after vaccination
  • Assessment of adverse events and serious adverse events [ Time Frame: 28 days post-vaccination ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 12, 2016)
  • Assessment of protection by PRNT50 [ Time Frame: 10 days post-vaccination ]
  • Duration of immunity [ Time Frame: 1 year post-vaccination ]
  • Assessment of adverse events and serious adverse events [ Time Frame: 28 days post-vaccination ]
    Brighton collaboration definitions will be used to assess adverse events following immunization. The investigation of SAE will follow WHO guidelines for "Detection and investigation of serious adverse events following yellow fever vaccination" WHO 2010
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Immunogenicity and Safety of Fractional Doses of Yellow Fever Vaccines (YEFE)
Official Title  ICMJE A Randomized, Blinded Non-inferiority Trial on the Immunogenicity and Safety of Fractional Doses of Yellow Fever Vaccines in Kenya and Uganda
Brief Summary

In July 2016, the demand for yellow fever vaccines in response to the large urban outbreaks occurring concurrently and the risk of further spread through the African continent and even to Asia, was larger than the available supply. In this situation, the World Health Organization (WHO) developed recommendations for the use of fractional-dose of yellow fever vaccine as a dose-sparing strategy. These recommendations were based on limited number of clinical trials and additional studies should assess the applicability of the fractional dose to all WHO-prequalified vaccines, the persistence of neutralizing antibodies and the performance of the fractional dose in young children and populations in Africa including those with HIV.

This study aims to respond to some of the research questions that would allow broadening the recommendations on the use of fractional doses of yellow fever vaccine in emergency situations. The study will be conducted in Uganda and Kenya and the main objective is to assess the non-inferiority is seroconversion 28 days after vaccination of a fractional dose compared to full dose for each WHO-prequalified manufacturer. As secondary objectives the study will assess seroprotection 10 days and 1 year after vaccination, to assess rapidity and persistence of protective antibody levels; describe the geometric mean titre and the change in neutralizing antibody on Day 28 days after vaccination with fractional and full doses; and assess the occurrence of adverse events and serious adverse events (SAE) during 28 days after administration of fractional and full doses.

The study consists of a randomized non-inferiority trial. The study aims to start in April 2017 in the two sites and aims to recruit 960 adults. Results for the main outcome will be reviewed by the study Data and Safety Monitoring Board and one vaccine will be selected for the studies in children and HIV positive adults.

Detailed Description

Yellow fever (YF) is a mosquito-borne viral disease that is endemic in 34 countries in the African region and 14 in South America. YF virus infection can be asymptomatic or cause a wide spectrum of disease, from mild symptoms to severe, potentially lethal illness with jaundice, renal failure and haemorrhage. The vast majority of reported cases and deaths occur in sub-Saharan Africa where yellow fever is a major health problem occurring in epidemic patterns. There is no specific treatment for yellow fever infection. However, YF vaccine is shown to be very effective for outbreak control as well as for the prevention of outbreaks. YF vaccination confers protection in most vaccinated individuals and this is considered to be life-long.

In 2016, YF outbreaks occurred in Africa (Angola, Democratic Republic of Congo (DRC) and Uganda) as well as in South America (Brazil, Colombia and Peru). Factors such increased urbanization in poor areas without proper water and sanitation systems and population movements, have the potential to contribute to increasing incidence of yellow fever and large epidemics. In July 2016, the demand for yellow fever vaccines in response to the large urban outbreaks occurring concurrently and the risk of further spread through the African continent and even to Asia, was larger than the available supply. In this situation, the World Health Organization (WHO) developed recommendations for the use of fractional-dose of yellow fever vaccine as a dose-sparing strategy. This strategy consisted on delivering 1/5th of the conventional dose and was used to vaccinate over 7 million people in Kinshasa, the capital city of DRC.

The evidence to recommend the use of fractional dosing was based on a limited number of clinical studies. However this was considered sufficient to provide emergency recommendations. In order to broaden and also possibly simplify WHO recommendations of fractional dose use in case of need for emergency campaigns, additional data is needed to respond to the important data gaps. These include the applicability of the fractional dose to all WHO-prequalified vaccines, the persistence of neutralizing antibodies and the performance of the fractional dose in young children and populations in Africa including those with HIV. Following these data gaps, WHO called for research to be conducted.

This study aims to respond to some of the research questions that would allow to broaden the recommendations on the use of fractional doses of yellow fever vaccine in emergency situations. The study will be conducted in Uganda and Kenya and the main objective is to assess the non-inferiority is seroconversion 28 days after vaccination of a fractional dose compared to full dose for each manufacturer. As secondary objectives the study will assess seroprotection 10 days and 1 year after vaccination, to assess rapidity and persistence of protective antibody levels; describe the geometric mean titre and the change in neutralizing antibody on Day 28 after vaccination with fractional and full doses; and assess the occurrence of adverse events and serious adverse events (SAE) during 28 days after administration of fractional and full doses. The study aims to recruit 960 adults (480 in Mbarara, Uganda, and 480 in Kilifi, Kenya). Results for the main outcome will be reviewed by the study Data and Safety Monitoring Board (DSMB) and if results are considered satisfactory, the study will continue with the recruitment of 420 children in Uganda and 250 HIV infected adults in Kenya, to assess non-inferiority of one of the WHO prequalified vaccines.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Yellow Fever
Intervention  ICMJE
  • Biological: Stamaril, Sanofi Pasteur
    1. Full dose
    2. Fractional dose: one fifth (1/5)
  • Biological: Yellow fever vaccine, Bio-Manguinhos
    1. Full dose
    2. Fractional dose: one fifth (1/5)
  • Biological: Yellow fever vaccine, Institut Pasteur
    1. Full dose
    2. Fractional dose: one fifth (1/5)
  • Biological: Yellow fever vaccine, Chumakov Institute
    1. Full dose
    2. Fractional dose: one fifth (1/5)
  • Biological: Yellow fever vaccine, Chumakov Institute
    1. Full dose
    2. Fractional dose: one fifth (1/5)
    Other Name: Children sub-study
  • Biological: Yellow fever vaccine, Chumakov Institute
    1. Full dose
    2. Fractional dose: one fifth (1/5)
    Other Name: HIV + adults
Study Arms  ICMJE
  • Active Comparator: Stamaril, Sanofi Pasteur: Standard dose
    Subcutaneous administration of 1 dose of a standard yellow fever vaccine
    Intervention: Biological: Stamaril, Sanofi Pasteur
  • Experimental: Stamaril, Sanofi Pasteur: Fractional dose
    Subcutaneous administration of 1/5th of a standard dose of yellow fever vaccine
    Intervention: Biological: Stamaril, Sanofi Pasteur
  • Active Comparator: Yellow fever vaccine, Bio-Manguinhos: Standard dose
    Subcutaneous administration of 1 dose of a standard yellow fever vaccine
    Intervention: Biological: Yellow fever vaccine, Bio-Manguinhos
  • Experimental: Yellow fever vaccine, Bio-Manguinhos: Fractional dose
    Subcutaneous administration of 1/5th of a standard dose of yellow fever vaccine
    Intervention: Biological: Yellow fever vaccine, Bio-Manguinhos
  • Active Comparator: Yellow fever vaccine, Institut Pasteur: Standard dose
    Subcutaneous administration of 1 dose of a standard yellow fever vaccine
    Intervention: Biological: Yellow fever vaccine, Institut Pasteur
  • Experimental: Yellow fever vaccine, Institut Pasteur: Fractional dose
    Subcutaneous administration of 1/5th of a standard dose of yellow fever vaccine
    Intervention: Biological: Yellow fever vaccine, Institut Pasteur
  • Active Comparator: Yellow fever vaccine, Chumakov Institute: Standard dose
    Subcutaneous administration of 1 dose of a standard yellow fever vaccine
    Intervention: Biological: Yellow fever vaccine, Chumakov Institute
  • Experimental: Yellow fever vaccine, Chumakov Institute: Fractional dose
    Subcutaneous administration of 1/5th of a standard dose of yellow fever vaccine
    Intervention: Biological: Yellow fever vaccine, Chumakov Institute
  • Active Comparator: YF, Chumakov Institute: Standard dose in Children
    Subcutaneous administration of 1 dose of the yellow fever vaccine
    Intervention: Biological: Yellow fever vaccine, Chumakov Institute
  • Experimental: YF, Chumakov Institute: Fractional dose in Children
    Subcutaneous administration of 1/5th of a standard dose of yellow fever vaccine
    Intervention: Biological: Yellow fever vaccine, Chumakov Institute
  • Active Comparator: YF, Chumakov Institute: Standard dose in HIV+ adults
    Subcutaneous administration of 1 dose of the yellow fever vaccine
    Intervention: Biological: Yellow fever vaccine, Chumakov Institute
  • Experimental: YF, Chumakov Institute: Fractional dose in HIV+ adults
    Subcutaneous administration of 1/5th of a standard dose of yellow fever vaccine
    Intervention: Biological: Yellow fever vaccine, Chumakov Institute
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 27, 2018)
1630
Original Estimated Enrollment  ICMJE
 (submitted: December 12, 2016)
960
Estimated Study Completion Date  ICMJE December 31, 2020
Actual Primary Completion Date February 21, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adults population: 18 to 60 years of age
  • Children population: 9 to 59 months of age
  • For HIV positive population: HIV positive on serological testing
  • If HIV infection, CD4 T-cell counts ≥200 cells/mm³ for adults or CD4 percentage >25% for children
  • Providing informed consent to participate in the study

Exclusion Criteria:

  • Contraindications to yellow fever vaccination:
  • History of yellow fever vaccination
  • Previous yellow fever infection
  • Requiring yellow fever vaccination for travelling purposes
  • Pregnancy (as determined by a urine test on the proposed day of vaccination) and lactating women
  • Refusal to participate in the study
  • Planning to move out of the study area before the end of the study follow-up
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 9 Months to 60 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Aitana Juan-Giner, MSc +33140215497 aitana.juan@epicentre.msf.org
Contact: Marie-Françoise Scherrer, BSc +33140215516 mscherrer@epicentre.msf.org
Listed Location Countries  ICMJE Uganda,   Kenya
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02991495
Other Study ID Numbers  ICMJE YEFE_2017
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Epicentre
Study Sponsor  ICMJE Epicentre
Collaborators  ICMJE Kenya Medical Research Institute
Investigators  ICMJE Not Provided
PRS Account Epicentre
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP