Efficacy model for antibody-mediated pre-erythrocytic malaria vaccines

Abstract

Antibodies to the pre-erythrocytic antigens, circumsporozoite protein (CSP), thrombospondin-related adhesive protein (TRAP) and liver-stage antigen 1, have been measured in field studies of semi-immune adults and shown to correlate with protection from Plasmodium falciparum infection. A mathematical model is formulated to estimate the probability of sporozoite infection as a function of antibody titres to multiple pre-erythrocytic antigens. The variation in antibody titres from field data was used to estimate the relationship between the probability of P. falciparum infection per infectious mosquito bite and antibody titre. Using this relationship, we predict the effect of vaccinations that boost baseline CSP or TRAP antibody titres. Assuming the estimated relationship applies to vaccine-induced antibody titres, then single-component CSP or TRAP antibody-mediated pre-erythrocytic vaccines are likely to provide partial protection from infection, with vaccine efficacy of approximately 50 per cent depending on the magnitude of the vaccine-induced boost to antibody titres. It is possible that the addition of a TRAP component to a CSP-based vaccine such as RTS,S would provide an increase in infection-blocking efficacy of approximately 25 per cent should the problem of immunological interference between antigens be overcome.

Figure 1.

Example dose–response curves. Dose–response curves for the probability of sporozoite survival as a function of IgG antibody titre. The solid and dashed curves depict a convex dose–response relationship where the antibody is effective even at low levels. The dotted curve depicts a threshold dose–response curve where the antibody only becomes effective once a threshold has been reached. Solid line, exponential; dashed line, convex Hill; dotted line, threshold Hill.

Figure 2.

Estimated exponential dose–response curves for the relationship between probability of sporozoite survival and IgG antibody titre to each of the antigens CSP, TRAP and LSA-1. Dashed lines represent 95% CI for estimates. Green curve, CSP; blue curve, TRAP; red curve, LSA-1.

Figure 3.

Estimated distribution of infection probability per infectious bite in the study population. The variation in infection probability represented here is owing only to variation in the CSP, TRAP and LSA-1 IgG antibody titres.

Figure 4.

Predicted pre-erythrocytic vaccine efficacy using fixed boost vaccination. The maximum CSP and TRAP titres observed in the study participants are marked to indicate the vaccine efficacy that could be obtained by giving a boost equal to the maximum observed antibody titre. Dashed lines represent 95% CI. Green curves, CSP; blue curves, TRAP; red curves, CSP+TRAP.

Figure 5.

Predicted vaccine efficacy as a function of baseline antibody titre. The average baseline antibody titre relative to the study site at Kanyawegi is used as a marker of transmission intensity. Dashed lines represent 95% CI. Green curves, CSP; blue curves, TRAP; red curves, CSP+TRAP.