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While live oral rotavirus vaccines (LORVs) are effective at preventing severe rotavirus gastroenteritis (SRVGE), they perform sub-optimally in the settings with the highest burden. Parenteral rotavirus vaccines could have greater efficacy by bypassing the gut, where interference with LORVs may occur. A novel parenteral rotavirus subunit vaccine (TV P2-VP8) was evaluated in a Phase 3 study for safety, immunogenicity, and relative efficacy in healthy African infants. Participating infants were randomized at 6–8 weeks of age to receive either three doses of TV P2-VP8 intramuscularly (IM) plus oral placebo or two doses of ROTARIX® (oral) plus IM placebo. The trial was designed to enroll a total of 8200 participants in two stages separated by an interim analysis conducted upon accrual of a predetermined number of SRVGE cases. Data at interim analysis indicated a low probability of demonstrating TV P2-VP8 superiority compared to ROTARIX in prevention of SRVGE, and the study was closed early. 4055 infants were enrolled and provided safety data. TV P2-VP8 was safe and well tolerated, with no safety concerns indicated. Virus neutralizing and IgG binding antibody seroresponses to TV-P2-VP8 were detected in most participants. The crude attack rates of SRVGE in the per-protocol population (n = 3477) were 4.51 % (TV P2-VP8) and 2.57 % (ROTARIX). The relative vaccine efficacy (RVE) against SRVGE for TV P2-VP8 was −77.68 % (95 % CI, −162.38, −21.54). The RVE against SRVGE in the first and second year of life was −91.67 % (95 % CI, −199.20, −24.35) and − 31.97 % (95 % CI, −220.37, 44.49), respectively. The RVE against rotavirus gastroenteritis of any severity was −47.78 % (95 % CI, −89.63, −15.59). TV P2-VP8 provided inferior protection against SRVGE compared to ROTARIX. The vaccine candidate was safe, immunogenic, and well-tolerated by infants. Continued efforts are needed to identify alternative rotavirus vaccines with improved efficacy in LMICs. Trial Registration:NCT04010448; PACTR201907491834482. •The TV P2-VP8 vaccine candidate was safe and immunogenic.•Three doses of TV P2-VP8 were inferior to two doses of ROTARIX® in preventing severe rotavirus gastroenteritis.•Study provides insight to guide future development of rotavirus vaccine candidates.