In 2015, the European Medicines Agency adopted a positive scientific opinion on RTS, S/AS01 (Mosquirix), the first malaria vaccine ever evaluated by a regulator. RTS, S is intended for immunization against Plasmodium falciparum malaria in endemic countries, in children aged 6 weeks to 17 months, and it is generally administered in 3 doses in a 0-1-2–month schedule [1]. However, protection against clinical malaria in phase 3 trials in this population reached only about 18%–36%[2], below the World Health Organization’s stated target of 75% for a malaria vaccine [3]. Moreover, protection was relatively lower in younger children and in areas with higher transmission intensity and was generally short-lived, waning largely within 3 years of immunization, but could be extended by a booster dose at 20 months. Concerns were raised over rare safety signals, including cerebral malaria, meningitis and increased all-cause mortality rate in girls [4]. To address these issues and to explore the practicalities of implementing

RTS, S/AS01 (including booster) into national immunization programs, the World Health Organization requested large-scale postlicensure trials before a final decision on recommending widescale implementation. These trials commenced in Ghana, Kenya, and Malawi in 2019 and will last until 2024. In parallel, various avenues are being explored to improve immunogenicity and ultimately protection. Strategies have included combining RTS, S with DNA [5] or viral vectors [6, 7] in a prime-boost regimen, or with other antigens [8]. Inspired by a somewhat overlooked finding from the original RTS, S trials in adult volunteers in the 1990s, Regules and colleagues [9] demonstrated enhanced protection against controlled human malaria infection (CHMI) in previously naive subjects if the RTS, S/AS01 regimen involved a third dose that was fractional (one-fifth normal) and delayed (0-1-7–month instead of 0-1-2–month schedule). In the largest CHMI study to date, described in this issue of The Journal of Infectious Diseases [10], Moon and colleagues have followed up on their concept by exploring the efficacy of different delayed fractional dosing regimens, including both the adult (RTS, S/AS01B) and pediatric formulation (RTS, S/ASO1E, which contains half the antigen and active adjuvant of RTS, S/AS01B). Overall, efficacy against CHMI with a homologous P. falciparum strain at 3 months