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

Abstract

BackgroundThe 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.MethodsQuantity 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.ResultsAfter 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).ConclusionsChange in IgG response between vaccine doses merits further evaluation as a surrogate marker for RTS,S efficacy.Trial registrationClinicalTrials.gov Identifier NCT00436007.

The RTS,S/AS01 malaria vaccine in children 5 to 17 months of age at first vaccination

“…In addition, similar anti-CS antibody kinetics were previously observed with a delayed third vaccine dose when RTS, S/AS01 was given according to a 0,1,7-month schedule in a phase II study [19]. Recent data from that study however suggest that increases in antibody concentrations and avidity following successive vaccinations are associated with a riskreduction for malaria [50].…”

Viral Vector Malaria Vaccines Induce High-Level T Cell and Antibody Responses in West African Children and Infants

“…In the Burkinabe infants, IgG1 avidity was significantly lower than in Gambian infants of the same age, perhaps again due to increased malaria exposure in Burkina Faso. Avidity of IgG antibodies alone has been shown not to be predictive of malaria vaccine efficacy for RTS,S/AS01, however, an association between the change in avidity, as well as IgG titers following the second and third dose were strongly associated with a reduction in the risk of malaria 45 . This suggests that the kinetics of antibody avidity maturation as well as the magnitude of the IgG response contributes to vaccine efficacy.…”

Th1 immune response to Plasmodium falciparum recombinant thrombospondin‐related adhesive protein (TRAP) antigen is enhanced by TLR3‐specific adjuvant, poly(I:C) in BALB/c mice

“…To date, in phase III clinical trials, P. falciparum CSP‐based vaccines (RTS,S) have shown moderate protection in children . This limitation may be due to poor immunogenicity of tested antigens that are unable to elicit strong inhibitory antibody responses . Therefore, attempts to develop an effective P. falciparum vaccine using other antigens are ongoing in different laboratories …”

“…3,59,60 This limitation may be due to poor immunogenicity of tested antigens that are unable to elicit strong inhibitory antibody responses. 61,62 Therefore, attempts to develop an effective P. falciparum vaccine using other antigens are ongoing in different laboratories. 40,63,64 An ideal pre-erythrocytic malaria vaccine should induce both cellular and humoural responses, including neutralizing, opsonizing and invasion inhibitory antibodies.…”