Fractional Dosing of Yellow Fever Vaccine to Extend Supply: A Modeling Study

Wu, Joseph T.; Peak, Corey M.; Leung, Gabriel M.; Lipsitch, Marc

The first is a randomized, noninferiority trial which showed that 0·1 ml intradermal (ID) vaccination with the 17D YF vaccine was equally safe and immunogenic compared to the standard 0·5ml subcutaneous vaccination. 8 The second is a randomized trial of subcutaneous administration of the 17DD vaccine given in Brazil which showed that there was no significant difference in immunogenicity and viremia kinetics when the currently administered vaccine (containing 27,476 IU of virus) was given at subdoses as low as 11% of the full dose (3,013 IU). 9 Even lower doses produced noninferior immune responses, but not equivalent viremia kinetics. 9 For comparison, the WHO minimum for YF vaccines is 1,000 IU per dose at the end of shelf life. 10 No efficacy trial of YF vaccines, however, has ever been performed in humans, 11 so the comparative efficacy of different doses and routes of administration remains uncertain. In particular, it is not known whether equal immunogenicity implies equal vaccine efficacy for YF vaccines. Moreover, the findings of equal immunogenicity of reduced doses are limited to healthy adults; no comparable data exist in children (thus the age cutoff of 2 years for fractional-dose vaccines in Kinshasa), elderly or immunocompromised individuals (e.g. HIV-infected people, pregnant women, etc.). As such, while noninferior immunogenicity of fractional-dose vaccines provide a strong basis for an initial consideration of dose-sparing strategies for YF vaccines, it would be prudent to ensure the robustness of this strategy by carefully evaluating the risk and epidemiologic impact of reduced vaccine efficacy in fractional-dose vaccines. Such an evaluation is nontrivial because even if dose fractionation reduces vaccine efficacy, higher vaccine coverage may confer higher herd immunity in which case the number of infections could be significantly reduced by the indirect effect of large-scale vaccination. 12 The lower the transmissibility, the larger the number of infections that can be averted by indirect protection, as illustrated by the previous study of dose fractionation for pre-pandemic influenza vaccines. 5 The importance of herd immunity for YF vaccination is unknown because transmissibility of YF in urban settings has never been adequately characterized due to limited data.