Fractional dosing of yellow fever vaccine to extend supply: a modelling study

Abstract

Background: The ongoing yellow fever epidemic in Angola strains the global vaccine supply, prompting WHO to adopt dose sparing for its vaccination campaign in Kinshasa, Democratic Republic of the Congo, in July-August, 2016. Although a 5-fold fractional-dose vaccine is similar to standard-dose vaccine in safety and immunogenicity, efficacy is untested. There is an urgent need to ensure the robustness of fractional-dose vaccination by elucidation of the conditions under which dose fractionation would reduce transmission.

Methods: We estimate the effective reproductive number for yellow fever in Angola using disease natural history and case report data. With simple mathematical models of yellow fever transmission, we calculate the infection attack rate (the proportion of population infected over the course of an epidemic) with various levels of transmissibility and 5-fold fractional-dose vaccine efficacy for two vaccination scenarios, ie, random vaccination in a hypothetical population that is completely susceptible, and the Kinshasa vaccination campaign in July-August, 2016, with different age cutoff for fractional-dose vaccines.

Findings: We estimate the effective reproductive number early in the Angola outbreak was between 5·2 and 7·1. If vaccine action is all-or-nothing (ie, a proportion of vaccine recipients receive complete protection [VE] and the remainder receive no protection), n-fold fractionation can greatly reduce infection attack rate as long as VE exceeds 1/n. This benefit threshold becomes more stringent if vaccine action is leaky (ie, the susceptibility of each vaccine recipient is reduced by a factor that is equal to the vaccine efficacy). The age cutoff for fractional-dose vaccines chosen by WHO for the Kinshasa vaccination campaign (2 years) provides the largest reduction in infection attack rate if the efficacy of 5-fold fractional-dose vaccines exceeds 20%.

Interpretation: Dose fractionation is an effective strategy for reduction of the infection attack rate that would be robust with a large margin for error in case fractional-dose VE is lower than expected.

Funding: NIH-MIDAS, HMRF-Hong Kong.

Conflict of interest statement

Declaration of interests JTW, CMP, and GML have no conflicts of interest.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Estimates of reproductive number over the course of the Angola epidemic

A Epidemic curve of confirmed cases by dates of symptom onset in Angola and vaccine coverage in Luanda province achieved by the reactive YF vaccination campaign that started on 2 February 2016. The first cases of this YF outbreak were identified in Luanda province which accounted for 90 of the 121 cases confirmed in Angola up to 26 February 2016. B–C Estimates of the daily reproductive number (Rt) assuming that the mean mosquito lifespan was 7 and 14 days, respectively. The red data points correspond to the cases that were used to estimate the initial reproductive number. These cases had symptom onset one mean serial interval before the vaccination campaign began to affect disease transmission (which was assumed to be 7 days after the start of the campaign to account for the time it takes for adaptive immunity to develop). The orange and purple horizontal bars indicate the length of the mean mosquito lifespan and serial interval on the scale of the x-axis, respectively.

Figure 2. The impact of five-fold fractional-dose vaccination with different vaccine efficacy and reproductive numbers

We assume that (i) the whole population is susceptible, (ii) vaccine action is all-or-nothing, and (iii) standard-dose vaccine efficacy is 1. If the standard-dose vaccine coverage V exceeds 20%, then everyone in the population can be vaccinated under five-fold fractionated-dose vaccination, in which case the fractionation would only be n = 1/V. A The effective vaccine coverage (VE(n) × nV), which is essentially the percentage of population immunized, as a function of standard-dose vaccine coverage V under standard-dose vaccination (solid curves) and five-fold fractional-dose vaccination (dashed curves). B Infection attack rate (IAR) under standard-dose vaccination and five-fold fractional-dose vaccination. IAR is reduced to 0 when the effective vaccine coverage reaches the herd immunity threshold 1−1/R0. C Absolute reduction in IAR. As V increases from 0, a kink appears when the herd-immunity threshold is attained or everyone is vaccinated under five-fold fractional-dose vaccination (i.e., V = 20%). If five-fold fractional-dose vaccination at 100% coverage cannot attain the herd immunity threshold (because of low fractional-dose vaccine efficacy), then a second kink appears when V is large enough such that fractional-dose vaccination attains herd-immunity threshold due to the increase in VE(n) resulting from lower fractionation (namely n = 1/V). D Relative reduction in IAR.

Figure 3. Benefit thresholds for leaky vaccines as a function of standard dose vaccine supply V and basic reproductive number R0

Five-fold fractionated dosing reduces IAR compared to standard dosing if the leaky vaccine efficacy of fractional-dose is above the threshold. This threshold becomes high for large values of R0 because under the “leaky” vaccine action model, multiple exposures eventually overcome vaccine protection and lead to infection of vaccinated individuals.

Figure 4. Evaluating the WHO dose-sparing strategy in the Kinshasa vaccination campaign in July–August 2016

A Effective vaccine coverage (i.e. the percentage of population immunized). The green line indicates the pre-campaign coverage. The black solid and dashed lines indicate the post-campaign coverage if vaccines are administered (i) in standard dose only (strategy S) and (ii) according to the WHO dose-sparing strategy with alternative age cutoffs for fractional-dose vaccines (strategy F). B IAR under strategy S and F for different R0. C–D Absolute and relative reduction in IAR.