BACKGROUNDMalaria remains a substantial public health burden among young children in sub-Saharan Africa and a highly efficacious vaccine eliciting a durable immune response would be a useful tool for controlling malaria. R21 is a malaria vaccine comprising nanoparticles, formed from a circumsporozoite protein and hepatitis B surface antigen (HBsAg) fusion protein, without any unfused HBsAg, and is administered with the saponin-based Matrix-M adjuvant. This study aimed to assess the safety and immunogenicity of the malaria vaccine candidate, R21, administered with or without adjuvant Matrix-M in adults naïve to malaria infection and in healthy adults from malaria endemic areas.METHODSIn this Article we report two phase 1, first-in-human trials. The first trial was a phase 1a open-label study in the UK evaluating the safety and immunogenicity of R21 administered either alone, or with 50 μg of Matrix-M. The second trial was a phase 1b randomised controlled trial in Burkina Faso. Adults had to be aged 18-50 years for enrolment in the phase 1a trial, and 18-45 years in the phase 1b trial. The phase 1a trial doses were 2 μg, 10 μg, and 50 μg R21/Matrix-M, and 50 μg R21 only. The phase 1b trial doses were 10 μg R21/Matrix-M and saline placebo. Matrix-M was always dosed at 50 μg. Phase 1b implemented block randomisation by randomisation into study groups by an independent statistician based at the University of Oxford using a randomisation code list with allocation concealment using opaque sealed envelopes. The primary objective of the phase 1a trial was to assess the safety and tolerability of R21 with and without Matrix-M. The primary objective of the phase 1b trial was to assess the safety and tolerability of R21 with Matrix-M. Both trials are registered with ClinicalTrials.gov, NCT02572388 for phase 1a and NCT02925403 for phase 1b, and are completed.FINDINGSBetween Oct 1, 2015, and Jan 3, 2017, 31 individuals were enrolled in the phase 1a study. Six individuals were assigned to receive 2 μg R21/Matrix-M, 11 to 10 μg R21/Matrix-M, ten to 50 μg R21/Matrix-M, and four to 50 μg R21 only. Between Aug 26, 2016, and Sept 28, 2017, 13 individuals were enrolled in the phase 1b study. Eight individuals were assigned to receive 10 μg R21/Matrix-M, and five to placebo. Vaccinations were well tolerated, and most local and systemic adverse events were mild. There were no serious adverse events deemed related to vaccination. Two serious adverse events occurred. The first in the 10 μg R21/Matrix-M group was worsening of previously undisclosed or undiagnosed palindromic rheumatism and was deemed unlikely to be related to vaccination and the second in the 2 μg R21/Matrix-M was hospital admission for an unplanned excision of a pre-existing Bartholin's cyst, also unrelated to vaccination. In the phase 1a study, a total of 21 adverse events were recorded in the 2 μg R21/Matrix-M group, 103 in the 10 μg R21/Matrix-M group, 94 in the 50 μg R21/Matrix-M group, and 21 in the 50 μg R21 alone group. In the phase 1b study, twelve adverse events were recorded in the 10 μg R21/Matrix-M group and 0 in the placebo group.INTERPRETATIONR21 with Matrix-M adjuvant has an acceptable safety profile. These data have formed the basis for efficacy testing of this vaccine.FUNDINGThe European Commission Framework 7 and The European & Developing Countries Clinical Trials Partnership.
