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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized, Blinded Non-inferiority Trial on the Immunogenicity and Safety of Fractional Doses of Yellow Fever Vaccines in Kenya and Uganda

Conditions
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Yellow Fever

Intervention / Treatment
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* Biological: Stamaril, Sanofi Pasteur
* Biological: Yellow fever vaccine, Bio-Manguinhos
* Biological: Yellow fever vaccine, Institut Pasteur
* Biological: Yellow fever vaccine, Chumakov Institute
* Biological: Yellow fever vaccine, Chumakov Institute
* Biological: Yellow fever vaccine, Chumakov Institute


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 9 Months
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Stamaril, Sanofi Pasteur: Standard dose<br>Subcutaneous administration of 1 dose of a standard yellow fever vaccine | Biological: Stamaril, Sanofi Pasteur<br>* Full dose Fractional dose: one fifth (1/5)<br>|
| Experimental: Stamaril, Sanofi Pasteur: Fractional dose<br>Subcutaneous administration of 1/5th of a standard dose of yellow fever vaccine | Biological: Stamaril, Sanofi Pasteur<br>* Full dose Fractional dose: one fifth (1/5)<br>|
| Active Comparator: Yellow fever vaccine, Bio-Manguinhos: Standard dose<br>Subcutaneous administration of 1 dose of a standard yellow fever vaccine | Biological: Yellow fever vaccine, Bio-Manguinhos<br>* Full dose Fractional dose: one fifth (1/5)<br>|
| Experimental: Yellow fever vaccine, Bio-Manguinhos: Fractional dose<br>Subcutaneous administration of 1/5th of a standard dose of yellow fever vaccine | Biological: Yellow fever vaccine, Bio-Manguinhos<br>* Full dose Fractional dose: one fifth (1/5)<br>|
| Active Comparator: Yellow fever vaccine, Institut Pasteur: Standard dose<br>Subcutaneous administration of 1 dose of a standard yellow fever vaccine | Biological: Yellow fever vaccine, Institut Pasteur<br>* Full dose Fractional dose: one fifth (1/5)<br>|
| Experimental: Yellow fever vaccine, Institut Pasteur: Fractional dose<br>Subcutaneous administration of 1/5th of a standard dose of yellow fever vaccine | Biological: Yellow fever vaccine, Institut Pasteur<br>* Full dose Fractional dose: one fifth (1/5)<br>|
| Active Comparator: Yellow fever vaccine, Chumakov Institute: Standard dose<br>Subcutaneous administration of 1 dose of a standard yellow fever vaccine | Biological: Yellow fever vaccine, Chumakov Institute<br>* Full dose Fractional dose: one fifth (1/5)<br>|
| Experimental: Yellow fever vaccine, Chumakov Institute: Fractional dose<br>Subcutaneous administration of 1/5th of a standard dose of yellow fever vaccine | Biological: Yellow fever vaccine, Chumakov Institute<br>* Full dose Fractional dose: one fifth (1/5)<br>|
| Active Comparator: YF, Chumakov Institute: Standard dose in Children<br>Subcutaneous administration of 1 dose of the yellow fever vaccine | Biological: Yellow fever vaccine, Chumakov Institute<br>* Full dose Fractional dose: one fifth (1/5)<br>* Other names: Children sub-study;|
| Experimental: YF, Chumakov Institute: Fractional dose in Children<br>Subcutaneous administration of 1/5th of a standard dose of yellow fever vaccine | Biological: Yellow fever vaccine, Chumakov Institute<br>* Full dose Fractional dose: one fifth (1/5)<br>* Other names: Children sub-study;|
| Active Comparator: YF, Chumakov Institute: Standard dose in HIV+ adults<br>Subcutaneous administration of 1 dose of the yellow fever vaccine | Biological: Yellow fever vaccine, Chumakov Institute<br>* Full dose Fractional dose: one fifth (1/5)<br>* Other names: HIV + adults;|
| Experimental: YF, Chumakov Institute: Fractional dose in HIV+ adults<br>Subcutaneous administration of 1/5th of a standard dose of yellow fever vaccine | Biological: Yellow fever vaccine, Chumakov Institute<br>* Full dose Fractional dose: one fifth (1/5)<br>* Other names: HIV + adults;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seroconversion by PRNT50 (Plaque Reduction Neutralization Test 50 value) | Plaque reduction neutralization test will be used to quantify the titer of neutralising antibody for the virus | 28 days post-vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of protection by PRNT50 (Plaque Reduction Neutralization Test 50 value) | Plaque reduction neutralization test will be used to quantify the titer of neutralising antibody for the virus | 10 days post-vaccination | 
| Duration of immunity | Assessment of duration of immunity at 1 year after vaccination | 1 year post-vaccination | 
| Assessment of adverse events and serious adverse events |  | 28 days post-vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epidemic response