Maria Lara-Escandell, Lina Sánchez, Dídac Macià, Chenjerai Jairoce, Maxmillian Mpina, Hermann Sorgho, Sélidji Todagbé Agnandji, David Dosoo, Ben Gyan, Marta Vidal, Alfons Jiménez, Robert Andrew Mitchell, Daniel Medina-Expósito, Laura Puyol, Rebeca Santano, Sheetij Dutta, Seth Owusu‐Agyei, Kwaku Poku Asante, Halidou Tinto, Pedro Aíde, Augusto Nhabomba, Benjamin Mordmueller, Claudia Daubenberger, Ruth Aguilar, John Waitumbi, Gemma Moncunill, Carlota Dobaño
Background The RTS,S/AS01 E malaria vaccine provides partial protection against Plasmodium falciparum , largely mediated by antibodies targeting the circumsporozoite protein. Correlates of protection remain incompletely defined and have focused mainly on peak IgG responses to the immunodominant NANP-repeats, with less known about antibody durability or responses to the C-terminus of circumsporozoite protein. Methods In this observational study, we evaluated IgG responses to NANP-repeat, C-terminus, and full-length circumsporozoite protein constructs at five timepoints before and after primary and booster vaccination, in children aged 5–17 months from six African countries enrolled in the RTS,S/AS01 E phase 3 trial (NCT00866619, 2009–11). Antibody kinetics were analysed with linear regressions, and associations with clinical malaria risk over 1 year with Cox models. Findings Between May 25, 2009, to March 5, 2010, 1292 children were recruited and included for analysis in this study. IgG levels declined more slowly for C-terminus than for NANP-repeat over 17 months after primary vaccination (geometric mean fold change 0·099 [95% CI 0·089–0·110] vs 0·055 [0·048–0·062]; p<0·0001). The booster significantly enhanced C-terminal IgG, exceeding post-primary peak levels (geometric mean fold change 1·98 [95% CI 1·77–2·21]), whereas NANP-repeat responses were restored but remained below post-primary levels (geometric mean fold changes 0·57 [95% CI 0·51–0·63]). Higher circumsporozoite protein IgG levels correlated with reduced malaria risk, particularly during maintenance phases, with stronger associations for C-terminus, which remained independently protective after adjustment for NANP-repeat antibodies (hazard ratio 0·60, 95% CI 0·43–0·83; p=0·0021). After boosting, maintenance but not peak IgG levels correlated with reduced malaria risk. Interpretation IgG to circumsporozoite protein C-terminus are more durable than those to the NANP-repeats. Antibody maintenance emerges as a stronger predictor of RTS,S/AS01 E vaccine efficacy than peak responses. Funding USA National Institute of Allergy and Infectious Diseases, National Institutes of Health; PATH and Malaria Vaccine Initiative; Spanish Ministerio de Economía y Competitividad; Instituto de Salud Carlos III; CERCA programme; and Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement, Generalitat de Catalunya.