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

Abstract

BackgroundClinically protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants.Methodology/Principal FindingsWe 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/SignificanceWe 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 for accelerated local eliminations of malaria, and significantly increases potential for eradication.

Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8 + T Cell Responses

“…In a model OVA antigen system, mosquito bites induced mast cell degranulation and IL-10-mediated immunosuppression of antigen-specific T cell responses even 7 days after mosquito bite exposure (23). Others have also postulated that skin stage-initiated immunosuppression could explain reduced efficacy of malaria vaccines in endemic settings (24). These studies further demonstrate that mosquito component(s) alter the outcome of infection.…”

Enhancement of naturally acquired immunity against malaria by drug use

“…Some have argued that exposure to Plasmodium-infected mosquito bites induces malaria-specific regulatory T-cells in the skin and, therefore, parasite-specific immunotolerance, which blocks vaccine efficacy. Chloroquine may inhibit this induction of regulatory T-cells and, therefore, enhance the acquisition of immunity (Guilbride et al, 2010). As such, the known immune-modulating effects of the drug chloroquine may be, at least partially, responsible for the efficient induction of immunity in the CHMI model (Sauerwein et al, 2010).…”

Active migration and passive transport of malaria parasites

“…When arriving at the subcapsular sinus of lymph nodes, they appear to actively glide again and eventually encounter phagocytic cells that appear to clear the vast majority of parasites [10]. Because only few sporozoites are injected into the skin during natural bites, and only about 20% of these enter the lymphatic system [10,15], it is not clear if there is an immune response to these parasites -and if so whether it would be of a tolerogenic or activating nature [36,37]. However, during immunization regimes where sporozoites are used as live attenuated parasite vaccines, the large number of parasites arriving at the lymph node does elicit protective immune responses in mice [36,38].…”