The anti-circumsporozoite antibody response to repeated, seasonal booster doses of the malaria vaccine RTS,S/AS01E

Abstract

The recently deployed RTS,S/AS01_E malaria vaccine induces a strong antibody response to the circumsporozoite protein (CSP) on the surface of the Plasmodium falciparum sporozoite which is associated with protection. The anti-CSP antibody titre falls rapidly after primary vaccination, associated with a decline in efficacy, but the antibody titre and the protective response can be partially restored by a booster dose of vaccine, but this response is also transitory. In many malaria- endemic areas of Africa, children are at risk of malaria, including severe malaria, until they are five years of age or older and to sustain protection from malaria for this period by vaccination with RTS,S/AS01_E, repeated booster doses of vaccine may be required. However, there is little information about the immune response to repeated booster doses of RTS,S/AS01_E. In many malaria-endemic areas of Africa, the burden of malaria is largely restricted to the rainy season and, therefore, a recent trial conducted in Burkina Faso and Mali explored the impact of repeated annual booster doses of RTS,S/AS01_E given immediately prior to the malaria transmission season until children reached the age of five years. Anti-CSP antibody titres were measured in sera obtained from a randomly selected subset of children enrolled in this trial collected before and one month after three priming and four annual booster doses of vaccine using the GSK ELISA developed at the University of Ghent and, in a subset of these samples, by a multiplex assay developed at the University of Oxford. Three priming doses of RTS,S/AS01_E induced a strong anti-CSP antibody response (GMT 368.9 IU/mL). Subsequent annual, seasonal booster doses induced a strong, but lower, antibody response; the GMT after the fourth booster was 128.5 IU/mL. Children whose antibody response was in the upper and middle terciles post vaccination had a lower incidence of malaria during the following year than children in the lowest tercile. Results obtained with GSK ELISA and the Oxford Multiplex assay were strongly correlated (Pearson's correlation coefficient, r = 0.94; 95% CI, 0.93-0.95). Although anti-CSP antibody titres declined after repeated booster doses of RTS,S/AS01_E a high, although declining, level of efficacy was sustained suggesting that there may have been changes in the characteristics of the anti-CSP antibody following repeated booster doses.Clinical Trials Registration. NCT03143218.

Fig. 1. Anti-CSP antibody responses to priming and booster doses of the RTS,S/AS01_E malaria vaccine.

Anti-CSP IgG antibody titres as measured by the GSK ELISA in individual children pre- and post-priming vaccination (2017) and pre and post first (2018), second (2019), third (2020) and fourth (2021) booster seasonal vaccination doses shown by country. Results from Burkina Faso are shown in red, those from Mali in blue. CSP circumsporozoite, EU enzyme linked immunosorbent assay unit.

Fig. 2. Anti-CSP antibody responses to priming and booster doses of the RTS,S/S01_E malaria vaccine by gender and age at the time of vaccination.

Anti-CSP antibody titres measured by the GSK ELISA in individual children pre- and post-priming vaccination (2017) and pre and post first (2018), second (2019), third (2020) and fourth (2021) booster seasonal vaccination doses are shown by country. Results from children in the Burkina Faso study are shown in red, children in the Mali study are shown in blue. The top panels show titres of male and female children, and the lower panels show titres of younger and older children (age at first vaccination). CSP circumsporozoite, EU enzyme linked immunosorbent assay unit. Only a few children who had been aged 11 months of age at the time of first vaccination were eligible for vaccination in 2021, having reached the age of five years when they were no longer eligible to receive RTS,S/AS01_E or SMC in 2021. Consequently, there were only a few vaccinated children in the randomly selected group of children for the immunology serology sub-study in 2021 who had been 11 months old or older at the time of first vaccination.

Fig. 3. Comparison of anti-CSP antibody titres obtained in sera obtained from children vaccinated with the RTS,S/AS01_E vaccine using different ELISA assays.

Scatterplots showing correlations between titres of anti-CSP IgG antibodies in children vaccinated with RTS,S/AS01_E in log10 IU/AU/mL between the GSK ELISA and Oxford MSD ELISA, combined and stratified by study year (A: Combined 2017–2021; B: 2017; C: 2018; D: 2019; E: 2020, and F: 2021).

Fig. 4. Bland-Altman plots for Oxford MSD and GSK assays.

The blue line corresponds to the mean difference while the dotted horizontal green and red lines correspond to the 95% limits of agreement. The y-axis represents the difference between titres using Oxford MSD and the GSK ELISA, the X-axis represents the mean of the titres using the two assays.

Fig. 5. Schematic showing the interventions given to children in each of the three trial groups and their timing in relation to the malaria transmission seasons in 2017–2021.

Red arrows indicate blood sampling for serology, black arrows indicate vaccination (placebo vaccines, dotted arrows; RTS,S/AS01_E, solid arrows), and bold black arrows end of transmission season surveys.