Fractional doses of yellow fever vaccines are non-inferior to standard doses in seroconversion at 28 days post-vaccination 

1. One-fifth fractional doses from all four live attenuated yellow fever virus vaccines met the non-inferiority criterion.

2. The most common treatment-related adverse events were headache (22.2%), fatigue (13.7%), myalgia (13.3%), and self-reported fever (9.0%). 

Evidence Rating Level: 1 (Excellent)

Study Rundown: Yellow fever is a mosquito-borne viral disease that is endemic in 44 countries. During the 2016 outbreak of yellow fever in Angola, concerns were raised surrounding the adequacy of vaccine supply. Currently, fractional dosing – to preserve the standard vaccine supply – has shown efficacy, but evidence is limited to a single sub-strain. This randomized, double-blind, non-inferiority trial assessed the immunogenicity and safety of one-fifth fractional dose compared to standard dose of four WHO-prequalified yellow fever vaccines from three sub-strains. Primary outcome for this study was the proportion of participants with seroconversion 28 days post-vaccination, while secondary outcomes included assessment of geometric mean titres (GMT), geometric mean fold increase (GMFI – the geometric mean of ratios of post-vaccination titre to pre-vaccination titre), and serious adverse events (SAEs). According to study results, fractional dose from all four vaccines met the non-inferiority criterion, defined as less than 10% decrease in seroconversion in fractional dose compare with standard dose groups at 28 days after vaccination. Prominent treatment-related adverse events were headache, fatigue, myalgia, and self-reported fever, with no study-vaccine related serious events. This study may benefit by employing a larger sample size to increase validity as each treatment group consisted of only 120 participants. Overall, this study provides important insight into the use of fractional dosing for all WHO-prequalified yellow fever vaccines in inducing seroconversion 28 days after vaccination.

Click to read the study in The Lancet

Relevant Reading: Immunogenicity of Fractional-Dose Vaccine during a Yellow Fever Outbreak — Final Report

In-depth [randomized controlled trial]: Between Nov 6, 2017, and Feb 21, 2018, 1029 patients were assessed for eligibility. Included patients were those aged 18-59 years with no contraindications for vaccination, no history of previous yellow fever vaccination or infection, not pregnant or lactating, and able to comply with study procedures. Altogether, 960 participants (120 per group) were randomly assigned to one of eight groups, corresponding to four vaccines at standard and fractional doses: Bio-Manguinhos-Fiocruz [BMF], Chumakov Institute of Poliomyelitis and Viral Encephalitides [CIPVE], Institut Pasteur Dakar [IPD], and Sanofi Pasteur [SP]. Among enrolled participants, the mean age was 35.7 years and 55.1% were female. 99.2% (n=952) of participants completed the 28 days post-vaccination visit, while 96.7% (n=928) completed the 1-year visit.

Seroconversion rates were high in all groups at 28 days, with at least 98.2% participants seroconverting in each group. The difference in seroconversion between fractional and standard dose groups was 1.71% (95% confidence interval [CI] -2.60 to 5.28) for the BMF vaccine, -0.90% (95% CI -4.24 to 3.13) for the CIPVE vaccine, 1.82% (95% CI -2.75 to 5.39) for the IPD vaccine, and 0.0% (95% CI -3.32 to 3.29) for the SP vaccine. Seroconversion rates remained high 1 year after vaccination, with 50% plaque reduction neutralization test (PRNT₅₀) titers ≥ 4 times that of baseline in 98-100% of participants who received a fractional dose. However, GMTs of neutralising antibodies at 10 days post-vaccination were lower in fractional dose groups than in standard dose groups for all vaccines except for the BMF vaccine. Nonetheless, at 28 days, titres were high in all groups. The most common related adverse events (AEs) were headache (22.2%), fatigue (13.7%), myalgia (13.3%), and pyrexia (9.0%). Altogether, 10 serious AEs were reported, but none were related to study vaccines. Findings from this study suggest that fractional dose of WHO-prequalified vaccines are a non-inferior option in cases of supply shortage during the yellow fever outbreak.

Image: PD

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