Why Functional Pre-Erythrocytic and Bloodstage Malaria Vaccines Fail: A Meta-Analysis of Fully Protective Immunizations and Novel Immunological Model

Background: Clinically protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants. Methodology/Principal Findings: We identify and evaluate 1916 immunization studies between 1965-February 2010, and exclude partially or nonprotective results to find 177 completely protective immunization experiments. Detailed reexamination reveals an unexpectedly mundane basis for selective vaccine failure: live malaria parasites in the skin inhibit vaccine function. We next show published molecular and cellular data support a testable, novel model where parasite-host interactions in the skin induce malaria-specific regulatory T cells, and subvert early antigen-specific immunity to parasite-specific immunotolerance. This ensures infection and tolerance to reinfection. Exposure to Plasmodium-infected mosquito bites therefore systematically triggers immunosuppression of endemic vaccine-elicited responses. The extensive vaccine trial data solidly substantiate this model experimentally. Conclusions/Significance: We conclude skinstage-initiated immunosuppression, unassociated with bloodstage parasites, systematically blocks vaccine function in the field. Our model exposes novel molecular and procedural strategies to significantly and quickly increase protective efficacy in both pipeline and currently ineffective malaria vaccines, and forces fundamental reassessment of central precepts determining vaccine development. This has major implications fo

A nonlocal coupled damage-plasticity model for the analysis of ductile failure

This paper presents a nonlocal coupled damage-plasticity model for the analysis of ductile fracture. The proposed model makes use of both damage mechanics and plasticity theories and hence is able to capture the pre-peak hardening and post-peak softening responses as well as the stiffness reduction of the material during the deformation and fracture processes. Nonlocal regularisation technique is used as an enhancement to the proposed damage-plasticity model to deal with softening related problems in the constitutive modelling and the failure analysis. Emphasis is put on the determination of model parameters with a novel calibration procedure, based on the experimental technique (Korsunsky and Kim, 2005) on the measurement of essential and non-essential works of fracture, proposed and effectively used for the model calibration. It is shown that all model parameters can be properly calibrated based on the proposed method, and experimental results, making the model attractive for practical applications. The proposed nonlocal model enables the stress update to be carried out pointwise, and hence facilitates the implementation of the model in existing finite element codes. Numerical examples are used to demonstrate the capability of the proposed model