Could Less Be More? Accounting for Fractional-Dose Regimens and Different Number of Vaccine Doses When Measuring the Impact of the RTS,S/AS01E Malaria Vaccine

Abstract Background The RTS,S/AS01E (RTS,S) malaria vaccine is recommended for children in malaria endemic areas. This phase 2b trial evaluates RTS,S fractional- and full-dose regimens in Ghana and Kenya. Methods In total, 1500 children aged 5–17 months were randomized (1:1:1:1:1) to receive RTS,S or rabies control vaccine. RTS,S groups received 2 full RTS,S doses at months 0 and 1 and either full (groups R012-20, R012-14-26) or fractional doses (one-fifth; groups Fx012-14-26, Fx017-20-32). Results At month 32 post-dose 1, vaccine efficacy against clinical malaria (all episodes) ranged from 38% (R012-20; 95% confidence interval [CI]: 24%–49%) to 53% (R012-14-26; 95% CI: 42%–62%). Vaccine impact (cumulative number of cases averted/1000 children vaccinated) was 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), and 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional vs full dose; post hoc analysis), we estimated cases averted/1000 RTS,S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), and 880 (Fx017-20-32). Conclusions Vaccine efficacy was similar across RTS,S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If maintained through trial end, these observations underscore the means to reduce cost per regimen thus maximizing impact and optimizing supply. Clinical Trials Registration NCT03276962 (ClinicalTrials.gov). Full- and fractional-dose regimens of the RTS,S/AS01E malaria vaccine have similar vaccine efficacy against clinical malaria. With a fixed supply of vaccine, more children can be vaccinated and thus more cases prevented by using fractional- rather than full-dose regimens. The RTS,S/AS01E (RTS,S) malaria vaccine is currently the only malaria vaccine recommended for use in children from areas with moderate to high risk of malaria. We are conducting a trial in children in Ghana and Kenya to compare regimens with the third and subsequent RTS,S doses reduced to one-fifth and/or delayed vs the standard regimen, full-dose regimens, and a control vaccine. While we did not demonstrate superior vaccine efficacy of fractional- vs full-dose regimens, we showed that all RTS,S regimens provided substantial protection against malaria and were immunogenic and well tolerated during 32 months from the first RTS,S dose. We also calculated vaccine impact, measured as the number of malaria cases prevented for each 1000 c