Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial

Abstract

Background: The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014.

Methods: Using data from 8922 African children aged 5-17 months and 6537 African infants aged 6-12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time.

Findings: RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5-17 months than in those aged 6-12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6-12 weeks and higher immunogenicity in those aged 5-17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5-17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42-48) and that of the long-lived component was 591 days (557-632). After primary vaccination 12% (11-13) of the response was estimated to be long-lived, rising to 30% (28-32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98-153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity.

Interpretation: Anti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered.

Funding: UK Medical Research Council.

Figure 1

Anti-circumsporozoite antibody dynamics and association with efficacy against infection (A–D) Anti-circumsporozoite antibody dynamics after a primary schedule of RTS,S/AS01 with or without booster. The black bars denote the median and 95% ranges (2·5–97·5 percentile). The solid and dashed curves denote the median of the model predicted antibody titres. The dark and light shaded regions represent 50% and 95% of the model predicted variation in antibody titres. (E) Estimated dose–response relationship for the association between anti-CS antibody titre and efficacy against infection. (F) Estimated vaccine efficacy profile for infection based on waning antibody titres. CS=circumsporozoite. R3C=three doses of RTS,S/AS01 and a booster with a comparator vaccine. R3R=three doses of RTS,S/AS01 and a booster with RTS,S/AS01.

Figure 2

Vaccine efficacy profile for clinical malaria in children aged 6–12 weeks Data are point estimates of efficacy with 95% CIs, presented in 6 month and 3 month windows in low and high transmission sites, respectively. Kilifi, Korogwe, Bagamoyo, Lambarene, Manhica, and Lilongwe are low transmission sites. Agogo, Kombewa, Kintampo, Siaya, and Nanoro are high transmission sites. Cases of malaria are based on the primary case definition in the per-protocol population from 2·5 months to study end. The posterior median estimates of efficacy against clinical malaria predicted by the antibody dynamics model are presented in red. R3C=three doses of RTS,S/AS01 and a booster with a comparator vaccine. R3R=three doses of RTS,S/AS01 and a booster with RTS,S/AS01.

Figure 3

Vaccine efficacy profile for clinical malaria in children aged 5–17 months Data are point estimates of efficacy with 95% CIs, presented in 6 month and 3 month windows in low and high transmission sites, respectively. Kilifi, Korogwe, Bagamoyo, Lambarene, and Lilongwe are low transmission sites. Agogo, Kombewa, Kintampo, Siaya, and Nanoro are high transmission sites. There were no data for infants aged 5–17 months Manhica in the per-protocol cohort. Cases of malaria are based on the primary case definition in the per-protocol population from 2·5 months to study end. The posterior median estimates of efficacy against clinical malaria predicted by the antibody dynamics model are presented in red. R3C=three doses of RTS,S/AS01 and a booster with a comparator vaccine. R3R=three doses of RTS,S/AS01 and a booster with RTS,S/AS01.