Duration and association with protection of NANP-repeat-specific and C-terminus-specific anti-circumsporozoite protein IgG responses following RTS,S/AS01E vaccination: an observational ancillary immunological study of a phase 3 clinical trial.

BACKGROUND

The RTS,S/AS01E 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/AS01E 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/AS01E 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.