Immunogenicity of Fractional-Dose Vaccine during a Yellow Fever Outbreak - Final Report

Abstract

Background: In 2016, the response to a yellow fever outbreak in Angola and the Democratic Republic of Congo led to a global shortage of yellow fever vaccine. As a result, a fractional dose of the 17DD yellow fever vaccine (containing one fifth [0.1 ml] of the standard dose) was offered to 7.6 million children 2 years of age or older and nonpregnant adults in a preemptive campaign in Kinshasa. The goal of this study was to assess the immune response to the fractional dose in a large-scale campaign.

Methods: We recruited participants in four age strata at six vaccination sites. We assessed neutralizing antibody titers against yellow fever virus in blood samples obtained before vaccination and at 1 month and 1 year after vaccination, using a plaque reduction neutralization test with a 50% cutoff (PRNT₅₀). Participants with a PRNT₅₀ titer of 10 or higher were considered to be seropositive. Those with a baseline titer of less than 10 who became seropositive at follow-up were classified as having undergone seroconversion. Participants who were seropositive at baseline and who had an increase in the titer by a factor of 4 or more at follow-up were classified as having an immune response.

Results: Among 716 participants who completed the 1-month follow-up, 705 (98%; 95% confidence interval [CI], 97 to 99) were seropositive after vaccination. Among 493 participants who were seronegative at baseline, 482 (98%; 95% CI, 96 to 99) underwent seroconversion. Among 223 participants who were seropositive at baseline, 148 (66%; 95% CI, 60 to 72) had an immune response. Lower baseline titers were associated with a higher probability of having an immune response (P<0.001). Among 684 participants who completed the 1-year follow-up, 666 (97%; 95% CI, 96 to 98) were seropositive for yellow fever antibody. The distribution of titers among the participants who were seronegative for yellow fever antibody at baseline varied significantly among age groups at 1 month and at 1 year (P<0.001 for both comparisons).

Conclusions: A fractional dose of the 17DD yellow fever vaccine was effective at inducing seroconversion in participants who were seronegative at baseline. Titers remained above the threshold for seropositivity at 1 year after vaccination in nearly all participants who were seropositive at 1 month after vaccination. These findings support the use of fractional-dose vaccination for outbreak control. (Funded by the U.S. Agency for International Development and the Centers for Disease Control and Prevention.).

Figure 1.. Enrollment and Follow-up.

Of the 40 eligible participants who were excluded from the 1-month analysis, 21 (52%) were female. Of the excluded participants, 20 (50%) were between the ages of 2 and 5 years, 4 (10%) were between the ages of 6 and 12 years, 7 (18%) were between the ages of 13 and 49 years, and 9 (22%) were 50 years of age or older. Investigation by the Ministry of Health determined that the single death that occurred between enrollment and 1-month follow-up was related to a cardiac event and not to vaccination. Of the 32 participants who were excluded from the 1-year analysis, 20 (63%) were female; 11 (34%) were between the ages of 2 and 5 years, 6 (19%) were between the ages of 6 and 12 years, 5 (16%) were between the ages of 13 and 49 years, and 10 (31%) were 50 years of age or older. None of the 5 deaths that occurred between the 1-month and 1-year follow-up were determined to be related to the yellow fever vaccination.

Figure 2.. Immune Response and Geometric Mean Titer at 1-Month Follow-up among 223 Participants Who Were Seropositive at Baseline.

Panel A shows the proportion of participants who had an immune response 1 month after fractional-dose vaccination against yellow fever, according to the geometric mean titer of neutralizing antibodies at baseline. Panel B shows the geometric mean titer at 1-month follow-up according to the titer at baseline. In both panels, I bars indicate 95% confidence intervals. Data regarding the geometric mean titer at 1-year follow-up are provided in Figure S1 in the Supplementary Appendix.