Protocol No: ECCT/19/03/04 Date of Protocol: 04-03-2019

Study Title:

Non-Inferiority Fractional-Doses Trial For Yellow Fever Vaccine


Study Objectives:

Primary objective To determine the lowest dose (1000, 500 and 250 IU/dose) of YF vaccine that is non-inferior to the full standard dose as measured by seroconversion using the PRNT50 assay at 28 days post-vaccination in an adult population. Secondary objective(s) • To describe the geometric mean PRNT50 titre (GMT) at 10 days, 28 days, 1 year and at 2 years post-vaccination of the different doses of the YF vaccine. • To describe the change in PRNT50 titre (i.e. the geometric mean fold increase (GMFI) as a continuous variable) between baseline and day 28 after vaccination with the different doses of the YF vaccine. • To map out key stakeholders’ priorities and perceptions regarding a change in policy towards the use of fractional doses of YF vaccine and their potential influence on policy process. • To measure neutralising antibody to other flaviviruses (including dengue, West Nile and zika viruses) on the baseline sample and determine the impact of these antibodies on YF vaccine immunogenicity. • To assess post-vaccination control of viremia by vaccine dose on samples collected at baseline, and on days 2, 3, 4, 5, 6, 7 and 10 after vaccination. • To determine the change in T and B cell immune responses between baseline and days 10 and 28 post-vaccination. • To determine the change in serum cytokine and chemokine levels between baseline and days 2, 3, 4, 5, 6, 7, 10 and 28 post-vaccination • To assess the occurrence of adverse events (AE) over 28 days after vaccination and serious adverse events throughout the duration of the study.

Laymans Summary:

Lay Title: A trial to determine the safety and immune response elicited by the reduced doses of yellow fever vaccine in comparison to full dose of the vaccine in Kenyan and Ugandan adults and children What is the problem/background? Yellow fever (YF) is a disease caused by a mosquito-borne flavivirus that is endemic in sub-Saharan Africa and tropical South America. YF virus infection can cause mild or severe illness, leading to jaundice, kidney failure, bleeding and death. The YF vaccine is shown to be very effective for disease control, including prevention of YF outbreaks. However insufficient vaccine is produced for routine use, and whilst a YF vaccine stockpile is reserved for outbreak control, this is frequently depleted. Measures to increase the global supply of YF vaccine are urgently needed. What questions are we trying to answer? The World Health Organization (WHO) has recommended consideration of using fractions of standard YF vaccine dose to be able to vaccinate more individuals with a given quantity of vaccine in outbreak situations when there are insufficient doses to vaccinate the population at risk. However, the actual minimal dose of YF vaccine needed to elicit an immune response has not been determined. In this study, we will assess whether the immune response and adverse events occurring after vaccination of adults and children with the standard full dose of YF vaccine are comparable to those observed after vaccination with one of three lower doses of vaccine aiming to establish a minimal dose. Further, to support the implementation of a future YF control strategy using lower doses of vaccine, we will evaluate the views and perceptions of different stakeholders involved in national or international vaccine policy regarding the use of lower doses of the YF vaccine. Where is the study taking place, how many people does it involve and how are they selected? The vaccination study will take place in Kilifi, Kenya and Mbarara, Uganda among healthy adults and children who have previously not had the YF vaccine and/or YF infection and have no contraindications for vaccination. In total, 480 adults (240 at each site) and 420 children aged 9 months to 5 years (210 at each site) will be included. To evaluate views and perceptions on the use of fractional YF vaccine doses we will approach and conduct discussions and interviews with various stakeholders in national vaccine policy in Kenya, Uganda, Senegal and other international institutions. What does the study involve for those who are in it? Participants who have previously not had the YF vaccine and/or YF infection will be screened for any significant health problems. Those found eligible to participate will then be randomized to receive a single dose of the standard full dose of YF vaccine (group 1) or any of the three lower doses (groups 2 to 4). Participants will then be required to attend follow up visits to have blood taken for tests to measure immune response to vaccination, the level YF vaccine in the body, and to be asked about any side effects. Vaccine policy stakeholders included in the study will be requested to participate in interviews at their convenience. What are the benefits and risks/costs of the study for those involved? The risks relate to the possibility of developing an allergic or other reaction upon administration of the YF vaccine. Serious adverse reactions to the vaccine are, however, rare. There are no immediate health benefits to individuals participating in this study other than information about their health. If there was a YF outbreak in the future, participants getting the full YF vaccine dose would be expected to be protected and there is a chance that participants who receive the lower dose would be protected against infection. We are not able to issue YF vaccination certificates to participants at the point of vaccination. If the participant travels to endemic areas and needs a YF vaccination certificate for proof of vaccination, they will be advised to be revaccinated at an authorized health facility in Kenya or Uganda, respectively. However, on completion of the study we will offer participants the possibility to receive a YF vaccination certificate. No safety concerns are reported with multiple doses of the vaccine. The vaccine policy stakeholders participating in the study will not be at any risk associated with the vaccine trial. Any costs they incur during the process of the study will be reimbursed as out of pocket expenses. How will the study benefit society? If any of the lower YF vaccine doses safely elicits immune response that are comparable to the full vaccine dose, then in effect this finding could have an impact on the number of doses that are produced, and substantially increase the number of doses that can be given based on the world’s currently available vaccine stock, and thereby enhance our ability to prevent and control YF outbreaks. The results from the interviews and discussions with vaccine policy stakeholders will support the development of a strategy to implement the use of lower YF vaccine doses for disease control. When does the study start and finish? The study will start upon receipt of ethical approval and will be completed 40 months later.

Abstract of Study:

In July 2016, the demand for yellow fever (YF) 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 Organization (WHO) developed recommendations for the use of fractional doses of YF 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. Additional studies were initiated to assess the applicability of fractional doses to all four WHO-prequalified YF vaccines with respect to vaccine immunogenicity in adults and children in Africa, including HIV positive adults. One such study, comparing full standard dose to 1/5th of standard dose of all four WHO-prequalified YF vaccines in adults ( number: NCT02991495), is currently ongoing at KEMRI CGMRC (see SERU protocol 3452) and Epicentre, Mbarara (UNCST HS 2237) and 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.

Here, in this new complementary study, we aim 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 CGMRC, Kilifi) and Uganda (Epicentre, Mbarara) with trial participants recruited at both sites, using vaccine from one WHO-prequalified manufacturer (Institut Pasteur de Dakar, Senegal). Our primary aim is to compare the immunogenicity of full standard dose of vaccine with three lower doses in adults, using seroconversion at 28 days post-vaccination, measured by plaque reduction neutralization assay (PRNT50), as the endpoint. Adult participants (n=480) will be randomized for vaccination with full standard dose or with approximately 1000, 500 or 250 IU of vaccine (i.e. 4 arms, 1:1:1:1 allocation ratio). Safety and immunogenicity results will then be reviewed by the study DSMB, and the lowest non-inferior dose selected for assessment in a sub-study in children (n=420) in comparison to full standard dose (i.e. 2 arms, 1:1 allocation ratio). Secondary objectives will include immunogenicity at 10 days, 1 year and 2 years post-vaccination, assessment of the influence of cross-reactive antibodies to other flaviviruses on vaccine immunogenicity, assessment of T and B cell immune responses, assessment of virological and immunological kinetics and occurrence of serious adverse events (SAE). In addition, we will assess the range of views and perceptions of key stakeholders in vaccine policy and implementation on lower vaccine dose usage during YF epidemics and routine use. We expect the data from this qualitative study to inform the implementation of policies relating to low-dose vaccine usage for the control of YF and other diseases (e.g. pneumococcal vaccines) where such strategies are in consideration.