BACKGROUND: The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose. METHODS:From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. FINDINGS:8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8-40·5) and 7396 occurred in the R3C group (28·3%, 23·3-32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, -23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9-31·5) and 5444 occurred in the R3C group (18·3%, 11·7-24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI -9·4 to 37·5) and 104 in the R3C group (10·3%, -17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children. INTERPRETATION: RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. FUNDING: GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative.
RCT Entities:
BACKGROUND: The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose. METHODS: From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. FINDINGS: 8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8-40·5) and 7396 occurred in the R3C group (28·3%, 23·3-32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, -23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9-31·5) and 5444 occurred in the R3C group (18·3%, 11·7-24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI -9·4 to 37·5) and 104 in the R3C group (10·3%, -17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children. INTERPRETATION:RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. FUNDING: GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative.
Authors: Selidji Todagbe Agnandji; Bertrand Lell; Solange Solmeheim Soulanoudjingar; José Francisco Fernandes; Béatrice Peggy Abossolo; Cornelia Conzelmann; Barbara Gaelle Nfono Ondo Methogo; Yannick Doucka; Arnaud Flamen; Benjamin Mordmüller; Saadou Issifou; Peter Gottfried Kremsner; Jahit Sacarlal; Pedro Aide; Miguel Lanaspa; John J Aponte; Arlindo Nhamuave; Diana Quelhas; Quique Bassat; Sofia Mandjate; Eusébio Macete; Pedro Alonso; Salim Abdulla; Nahya Salim; Omar Juma; Mwanajaa Shomari; Kafuruki Shubis; Francisca Machera; Ali Said Hamad; Rose Minja; Ali Mtoro; Alma Sykes; Saumu Ahmed; Alwisa Martin Urassa; Ali Mohammed Ali; Grace Mwangoka; Marcel Tanner; Halidou Tinto; Umberto D'Alessandro; Hermann Sorgho; Innocent Valea; Marc Christian Tahita; William Kaboré; Sayouba Ouédraogo; Yara Sandrine; Robert Tinga Guiguemdé; Jean Bosco Ouédraogo; Mary J Hamel; Simon Kariuki; Chris Odero; Martina Oneko; Kephas Otieno; Norbert Awino; Jackton Omoto; John Williamson; Vincent Muturi-Kioi; Kayla F Laserson; Laurence Slutsker; Walter Otieno; Lucas Otieno; Otsyula Nekoye; Stacey Gondi; Allan Otieno; Bernhards Ogutu; Ruth Wasuna; Victorine Owira; David Jones; Agnes Akoth Onyango; Patricia Njuguna; Roma Chilengi; Pauline Akoo; Christine Kerubo; Jesse Gitaka; Charity Maingi; Trudie Lang; Ally Olotu; Benjamin Tsofa; Philip Bejon; Norbert Peshu; Kevin Marsh; Seth Owusu-Agyei; Kwaku Poku Asante; Kingsley Osei-Kwakye; Owusu Boahen; Samuel Ayamba; Kingsley Kayan; Ruth Owusu-Ofori; David Dosoo; Isaac Asante; George Adjei; George Adjei; Daniel Chandramohan; Brian Greenwood; John Lusingu; Samwel Gesase; Anangisye Malabeja; Omari Abdul; Hassan Kilavo; Coline Mahende; Edwin Liheluka; Martha Lemnge; Thor Theander; Chris Drakeley; Daniel Ansong; Tsiri Agbenyega; Samuel Adjei; Harry Owusu Boateng; Theresa Rettig; John Bawa; Justice Sylverken; David Sambian; Alex Agyekum; Larko Owusu; Francis Martinson; Irving Hoffman; Tisungane Mvalo; Portia Kamthunzi; Ruthendo Nkomo; Albans Msika; Allan Jumbe; Nelecy Chome; Dalitso Nyakuipa; Joseph Chintedza; W Ripley Ballou; Myriam Bruls; Joe Cohen; Yolanda Guerra; Erik Jongert; Didier Lapierre; Amanda Leach; Marc Lievens; Opokua Ofori-Anyinam; Johan Vekemans; Terrell Carter; Didier Leboulleux; Christian Loucq; Afiya Radford; Barbara Savarese; David Schellenberg; Marla Sillman; Preeti Vansadia Journal: N Engl J Med Date: 2011-10-18 Impact factor: 91.245
Authors: Kent E Kester; James F Cummings; Opokua Ofori-Anyinam; Christian F Ockenhouse; Urszula Krzych; Philippe Moris; Robert Schwenk; Robin A Nielsen; Zufan Debebe; Evgeny Pinelis; Laure Juompan; Jack Williams; Megan Dowler; V Ann Stewart; Robert A Wirtz; Marie-Claude Dubois; Marc Lievens; Joe Cohen; W Ripley Ballou; D Gray Heppner Journal: J Infect Dis Date: 2009-08-01 Impact factor: 5.226
Authors: Kalifa Bojang; Paul Milligan; Margaret Pinder; Tom Doherty; Amanda Leach; Opokua Ofori-Anyinam; Marc Lievens; Kent Kester; Kurt Schaecher; W Ripley Ballou; Joe Cohen Journal: Hum Vaccin Date: 2009-04-22
Authors: Selidji Todagbe Agnandji; Bertrand Lell; José Francisco Fernandes; Béatrice Peggy Abossolo; Barbara Gaelle Nfono Ondo Methogo; Anita Lumeka Kabwende; Ayola Akim Adegnika; Benjamin Mordmüller; Saadou Issifou; Peter Gottfried Kremsner; Jahit Sacarlal; Pedro Aide; Miguel Lanaspa; John J Aponte; Sonia Machevo; Sozinho Acacio; Helder Bulo; Betuel Sigauque; Eusébio Macete; Pedro Alonso; Salim Abdulla; Nahya Salim; Rose Minja; Maxmillian Mpina; Saumu Ahmed; Ali Mohammed Ali; Ali Takadir Mtoro; Ali Said Hamad; Paul Mutani; Marcel Tanner; Halidou Tinto; Umberto D'Alessandro; Hermann Sorgho; Innocent Valea; Biébo Bihoun; Issa Guiraud; Berenger Kaboré; Olivier Sombié; Robert Tinga Guiguemdé; Jean Bosco Ouédraogo; Mary J Hamel; Simon Kariuki; Martina Oneko; Chris Odero; Kephas Otieno; Norbert Awino; Meredith McMorrow; Vincent Muturi-Kioi; Kayla F Laserson; Laurence Slutsker; Walter Otieno; Lucas Otieno; Nekoye Otsyula; Stacey Gondi; Allan Otieno; Victorine Owira; Esther Oguk; George Odongo; Jon Ben Woods; Bernhards Ogutu; Patricia Njuguna; Roma Chilengi; Pauline Akoo; Christine Kerubo; Charity Maingi; Trudie Lang; Ally Olotu; Philip Bejon; Kevin Marsh; Gabriel Mwambingu; Seth Owusu-Agyei; Kwaku Poku Asante; Kingsley Osei-Kwakye; Owusu Boahen; David Dosoo; Isaac Asante; George Adjei; Evans Kwara; Daniel Chandramohan; Brian Greenwood; John Lusingu; Samwel Gesase; Anangisye Malabeja; Omari Abdul; Coline Mahende; Edwin Liheluka; Lincoln Malle; Martha Lemnge; Thor G Theander; Chris Drakeley; Daniel Ansong; Tsiri Agbenyega; Samuel Adjei; Harry Owusu Boateng; Theresa Rettig; John Bawa; Justice Sylverken; David Sambian; Anima Sarfo; Alex Agyekum; Francis Martinson; Irving Hoffman; Tisungane Mvalo; Portia Kamthunzi; Rutendo Nkomo; Tapiwa Tembo; Gerald Tegha; Mercy Tsidya; Jane Kilembe; Chimwemwe Chawinga; W Ripley Ballou; Joe Cohen; Yolanda Guerra; Erik Jongert; Didier Lapierre; Amanda Leach; Marc Lievens; Opokua Ofori-Anyinam; Aurélie Olivier; Johan Vekemans; Terrell Carter; David Kaslow; Didier Leboulleux; Christian Loucq; Afiya Radford; Barbara Savarese; David Schellenberg; Marla Sillman; Preeti Vansadia Journal: N Engl J Med Date: 2012-11-09 Impact factor: 91.245
Authors: J Anthony G Scott; James A Berkley; Isaiah Mwangi; Lucy Ochola; Sophie Uyoga; Alexander Macharia; Carolyne Ndila; Brett S Lowe; Salim Mwarumba; Evasius Bauni; Kevin Marsh; Thomas N Williams Journal: Lancet Date: 2011-09-06 Impact factor: 79.321
Authors: Seth Owusu-Agyei; Daniel Ansong; Kwaku Asante; Sandra Kwarteng Owusu; Ruth Owusu; Naana Ayiwa Wireko Brobby; David Dosoo; Alex Osei Akoto; Kingsley Osei-Kwakye; Emmanuel Asafo Adjei; Kwadwo Owusu Boahen; Justice Sylverken; George Adjei; David Sambian; Stephen Apanga; Kingsley Kayan; Johan Vekemans; Opokua Ofori-Anyinam; Amanda Leach; Marc Lievens; Marie-Ange Demoitie; Marie-Claude Dubois; Joe Cohen; W Ripley Ballou; Barbara Savarese; Daniel Chandramohan; John Owusu Gyapong; Paul Milligan; Sampson Antwi; Tsiri Agbenyega; Brian Greenwood; Jennifer Evans Journal: PLoS One Date: 2009-10-02 Impact factor: 3.240
Authors: Nicholas J MacDonald; Vu Nguyen; Richard Shimp; Karine Reiter; Raul Herrera; Martin Burkhardt; Olga Muratova; Krishan Kumar; Joan Aebig; Kelly Rausch; Lynn Lambert; Nikiah Dawson; Jetsumon Sattabongkot; Xavier Ambroggio; Patrick E Duffy; Yimin Wu; David L Narum Journal: J Biol Chem Date: 2016-07-18 Impact factor: 5.157
Authors: Dmitri Kazmin; Helder I Nakaya; Eva K Lee; Matthew J Johnson; Robbert van der Most; Robert A van den Berg; W Ripley Ballou; Erik Jongert; Ulrike Wille-Reece; Christian Ockenhouse; Alan Aderem; Daniel E Zak; Jerald Sadoff; Jenny Hendriks; Jens Wrammert; Rafi Ahmed; Bali Pulendran Journal: Proc Natl Acad Sci U S A Date: 2017-02-13 Impact factor: 11.205