Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial
Authors: Mehreen S Datoo, Alassane Dicko, Halidou Tinto, Jean-Bosco Ouédraogo, Mainga Hamaluba, Ally Olotu, Emma Beaumont, Fernando Ramos Lopez, Hamtandi Magloire Natama, Sophie Weston, Mwajuma Chemba, Yves Daniel Compaore, Djibrilla Issiaka, Diallo Salou, Athanase M Some, Sharon Omenda, Alison Lawrie, Philip Bejon, Harish Rao, Daniel Chandramohan, Rachel Roberts, Sandesh Bharati, Lisa Stockdale, Sunil Gairola, Brian M Greenwood, Katie J Ewer, John Bradley, Prasad S Kulkarni, Umesh Shaligram, Adrian V S Hill, Almahamoudou Mahamar, Koualy Sanogo, Youssoufa Sidibe, Kalifa Diarra, Mamoudou Samassekou, Oumar Attaher, Amadou Tapily, Makonon Diallo, Oumar Mohamed Dicko, Mahamadou Kaya, Seydina Oumar Maguiraga, Yaya Sankare, Hama Yalcouye, Soumaila Diarra, Sidi Mohamed Niambele, Ismaila Thera, Issaka Sagara, Mala Sylla, Amagana Dolo, Nsajigwa Misidai, Sylvester Simando, Hania Msami, Omary Juma, Nicolaus Gutapaka, Rose Paul, Sarah Mswata, Ibrahim Sasamalo, Kasmir Johaness, Mwantumu Sultan, Annastazia Alexander, Isaac Kimaro, Kauye Lwanga, Mwajuma Mtungwe, Kassim Khamis, Lighton Rugarabam, Wilmina Kalinga, Mohammed Mohammed, Janeth Kamange, Jubilate Msangi, Batuli Mwaijande, Ivanny Mtaka, Matilda Mhapa, Tarsis Mlaganile, Thabit Mbaga, Rakiswende Serge Yerbanga, Wendkouni Samtouma, Abdoul Aziz Sienou, Zachari Kabre, Wendinpui Jedida Muriel Ouedraogo, G Armel Bienvenu Yarbanga, Issaka Zongo, Hamade Savadogo, Joseph Sanon, Judicael Compaore, Idrissa Kere, Ferdinand Lionel Yoni, Tewende Martine Sanre, Seydou Bienvenu Ouattara, Samuel Provstgaard-Morys, Danielle Woods, Robert W. Snow, Nyaguara Amek, Caroline J. Ngetsa, Lynette Isabella Ochola-Oyier, Jennifer Musyoki, Marianne Munene, Noni Mumba, Uche Jane Adetifa, Charles Mwangi Muiruri, Jimmy Shangala Mwawaka, Mwatasa Hussein Mwaganyuma, Martha Njeri Ndichu, Joseph Ochieng Weya, Kelvin Njogu, Jane Grant, Jayne Webster, Anand Lakhkar, N. Félix André Ido, Ousmane Traore, Marc Christian Tahita, Massa dit Achille Bonko, Toussaint Rouamba, D. Florence Ouedraogo, Rachidatou Soma, Aida Millogo, Edouard Ouedraogo, Faizatou Sorgho, Fabé Konate, Innocent Valea
Journal: The Lancet (2024)

BackgroundRecently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites.MethodsWe did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5–36 months) were enrolled and randomly assigned (2:1) to receive 5 μg R21 plus 50 μg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on ClinicalTrials.gov, NCT04704830, and is ongoing.FindingsFrom April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71–79; p<0·0001) at the seasonal sites and 68% (61–74; p<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71–78; p<0·0001) at the seasonal sites and 67% (59–73; p<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762–974) cases per 1000 children-years at seasonal sites and 296 (231–362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5–17 month age group compared with 18–36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73–84]; p<0·001) and standard (75% [65–83]; p<0·001) sites.InterpretationR21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa.FundingThe Serum Institute of India, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre, and Open Philanthropy.