The effect of immunization schedule with the malaria vaccine candidate RTS,S/AS01E on protective efficacy and anti-circumsporozoite protein antibody avidity in African infants

Anthony Ajua, Bertrand Lell, Selidji Todagbe Agnandji, Kwaku Poku Asante, Seth Owusu-Agyei, Grace Mwangoka, Maxmilliam Mpina, Nahya Salim, Marcel Tanner, Salim Abdulla, Johan Vekemans, Erik Jongert, Marc Lievens, Pierre Cambron, Chris F Ockenhouse, Peter G Kremsner, Benjamin Mordmüller, Anthony Ajua, Bertrand Lell, Selidji Todagbe Agnandji, Kwaku Poku Asante, Seth Owusu-Agyei, Grace Mwangoka, Maxmilliam Mpina, Nahya Salim, Marcel Tanner, Salim Abdulla, Johan Vekemans, Erik Jongert, Marc Lievens, Pierre Cambron, Chris F Ockenhouse, Peter G Kremsner, Benjamin Mordmüller

Abstract

Background: The malaria vaccine RTS,S induces antibodies against the Plasmodium falciparum circumsporozoite protein (CSP) and the concentration of Immunoglobulin G (IgG) against the repeat region of CSP following vaccination is associated with protection from P. falciparum malaria. So far, only the quantity of anti-CSP IgG has been measured and used to predict vaccination success, although quality (measured as avidity) of the antigen-antibody interaction shall be important since only a few sporozoites circulate for a short time after an infectious mosquito bite, likely requiring fast and strong binding.

Methods: Quantity and avidity of anti-CSP IgG in African infants who received RTS,S/AS01E in a 0-1-2-month or a 0-1-7-month schedule in a phase 2 clinical trial were measured by enzyme-linked immunosorbent assay. Antibody avidity was defined as the proportion of IgG able to bind in the presence of a chaotropic agent (avidity index). The effect of CSP-specific IgG concentration and avidity on protective efficacy was modelled using Cox proportional hazards.

Results: After the third dose, quantity and avidity were similar between the two vaccination schedules. IgG avidity after the last vaccine injection was not associated with protection, whereas the change in avidity following second and third RTS,S/AS01E injection was associated with a 54% risk reduction of getting malaria (hazard ratio: 0.46; 95% confidence interval (CI): 0.22-0.99) in those participants with a change in avidity above the median. The change in anti-CSP IgG concentration following second and third injection was associated with a 77% risk reduction of getting malaria (hazard ratio: 0.23, 95% CI: 0.11-0.51).

Conclusions: Change in IgG response between vaccine doses merits further evaluation as a surrogate marker for RTS,S efficacy.

Trial registration: ClinicalTrials.gov Identifier NCT00436007 .

Figures

Figure 1
Figure 1
CONSORT study flow chart.
Figure 2
Figure 2
Box-plot and single measurements of absolute AI at second and third vaccination using two vaccination schedules (012 or 017).
Figure 3
Figure 3
Box-plot and single measurements of difference in AI (dAI) between second and third vaccination using two vaccination schedules (012 or 017). Note that for the analysis of dAI only paired samples were used (n = 179).
Figure 4
Figure 4
Kaplan Meier plot of malaria episodes over time in participants classified as having high (black) or low (grey) dAI.

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