Immunogenicity and safety of fractional doses of yellow fever vaccines
Study design
A double-blind, randomised, non-inferiority trial
Context
In July 2016, global demand for yellow fever (YF) vaccines exceeded the available supply. Against this backdrop, the World Health Organisation (WHO) recommended the use of fractional doses of the YF vaccine in order to make the best use of available resources.
The aim of this study is to generate the data needed to support the use of fractional doses of any WHO-prequalified YF vaccine in emergency situations where standard doses are insufficient to protect at-risk populations. The priority is to determine whether a fractional dose (i.e. 1/5th), administered subcutaneously, is safe and capable of inducing an adequate immune response.
The study involves an adult population, children, and adults living with HIV.
Our role
Sponsor, scientific oversight, study site
Partners
- KEMRI-Wellcome Trust Research Programme in Kilifi, Kenya, in Kilifi, Kenya,
- Medical Research Council Unit in The Gambia (for the study on the durability of the immune response)
YEFE: Immunogenicity and safety of fractional dose yellow fever vaccines in the general population
The fractional dose was defined as one-fifth of a standard dose. Unvaccinated adults were randomly allocated to vaccines from different manufacturers and to different doses (standard or one-fifth) and were followed up at 10 days, 28 days and 1 year after vaccination to assess immunogenicity and safety.
Results
A total of 1,029 adult participants were selected and 960 were vaccinated (240 per manufacturer and 120 per dose). Overall, 55.1 per cent of participants were women and the mean age at recruitment was 35.7 years.
At baseline, 5.1% of participants tested positive for yellow fever using the PRNT50 test. Baseline characteristics did not differ significantly between the standard-dose and split-dose groups for each manufacturer. 28 days after vaccination, 99.4% of participants seroconverted. The maximum difference between the split-dose group and the standard-dose group was –6.1 per cent.
Conclusions
The fractional dose of the yellow fever vaccine meets the non-inferiority criteria for all prequalified manufacturers 28 days after vaccination. The reduced dose did not raise any safety concerns.
Publication
Immunogenicity and safety of fractional doses of yellow fever vaccines: a randomised, double-blind, non-inferiority trial.
NIFTY: Immunogenicity of a fractional dose yellow fever vaccine in seropositive children and adults
Methods
The paediatric sub-study was conducted at the Epicentre centre in Mbarara, Uganda, and the HIV sub-study was conducted at KEMRI in Kilifi, Kenya. Children aged between 9 months and 5 years, or HIV-positive adults with no contraindications to vaccination, were randomly allocated to receive either a standard dose or a fractional dose (1/5th) at each site. Participants were followed up 10 days, 28 days and 1 year after vaccination.
Results
In total, 433 children and 303 HIV-positive adults were assessed; of these, 420 and 250 were recruited respectively and randomised to receive a standard dose or a fractional dose. Twenty-eight days after vaccination, over 95 per cent of participants in each group had seroconverted, and the fractional doses met the non-inferiority criterion. The absolute difference in seroconversion in the per-protocol population between the split-dose and standard-dose groups was –2.42 (95% CI: –4.82, 0.7) in children and –2.56 (95% CI: –6.92 to 1.79) in HIV-positive adults. No difference was observed in the incidence of adverse events and serious adverse events between the two groups.
Conclusion
The fractional dose regimen met the non-inferiority criterion in children aged 9 months to 5 years and in HIV-positive adults who were not immunocompromised.
Impact
These results will support the extension of the current WHO recommendation regarding the use of fractional doses in the event of a shortage for HIV-positive children and adults.
Publications
Immunogenicity and safety of fractional doses of 17D-213 yellow fever vaccine in HIV-infected people in Kenya (YEFE): a randomised, double-blind, non-inferiority substudy of a phase 4 trial.
Immunogenicity and safety of fractional doses of 17D-213 yellow fever vaccine in children (YEFE): a randomised, double-blind, non-inferiority substudy of a phase 4 trial.
Duration of the immune response
Following on from the YEFE and NIFTY trials, this study aims to strengthen the scientific evidence in favour of administering the yellow fever vaccine in fractional doses, with a view to informing public health policy.
The duration of the protective immune response induced by a fractional dose regimen remains unclear to date. Furthermore, the available data on the persistence of immunity in children are contradictory, for both full-dose and fractional dose regimens.
The aim of this cross-sectional study is to measure levels of neutralising antibodies against the yellow fever (YF) virus in adults and children who took part in the YEFE and NIFTY studies. It will also incorporate the results of a non-inferiority trial currently underway in The Gambia, which is investigating the administration of fractional doses to infants.
The data collected will enable:
- an assessment of immune protection between 2 and 8 years after vaccination,
- a determination of the duration of immunity induced by split-dose regimens,
- and insights into the possible need for a booster dose.
Status
In progress
To find out more about this issue
https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(23)00594-6/fulltext
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(24)00008-2/abstract
