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

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

We consider the all-or-nothing YF vaccine action mechanism more likely than the leaky vaccine action model for the following reasons: based on the limited evidence on immunogenicity of fractional doses to date, we consider it unlikely that reducing the dose five-fold or perhaps further from current preparations would result in dramatically lower efficacy of the leaky type. Visual inspection of the data from a dose fractionation trial of the 17DD vaccine in Brazil shows that for doses down to 47× below the standard dose, the distribution of serologic responses was indistinguishable from those for the standard dose, suggesting that efficacy should be nearly equivalent to that for full doses. This was confirmed by the analysis of peak viremia, which was equivalent for standard dose and for doses down to 11% of the full dose (9-fold fractionation). It was further confirmed by peak cytokine responses, which were comparable to the standard dose for all cytokines tested, down to at least a 9-fold fractional dose. For even lower doses, the proportion seroconverting after vaccination was lower than the 97% observed for the full dose, but the antibody response among the seroconverters appears to be similar at all doses. 9 These data collectively suggest that down to approximately 9-fold fractional dosing of this vaccine the response should be equivalent, and that for further fractionation there may be a failure to induce any substantial response in a fraction of recipients, but the neutralizing antibody titres in those who do respond should be comparable. This pattern is consistent with an all-ornothing model.