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.

Reduced Plasmodium berghei sporozoite liver load associates with low protective efficacy after intradermal immunization

“…Moreover, GAP immunized IFNc) ⁄ ) mice produced sporozoite-specific antibodies but were not protected against a WT challenge (34). Overall, our findings corroborate the conclusions of a meta-analysis by Guilbride et al (35), emphasizing the poor capacity to induce protective efficacy after sporozoite inoculation via the skin as compared to the IV route. Although in human volunteers whole parasite immunization by bite of infected mosquitoes can induce complete protection (6,(36)(37)(38), mosquito bites are obviously not a practical route of immunization.…”

“…Overall, our findings corroborate the conclusions of a meta‐analysis by Guilbride et al. (35), emphasizing the poor capacity to induce protective efficacy after sporozoite inoculation via the skin as compared to the IV route.…”

Reduced Plasmodium berghei sporozoite liver load associates with low protective efficacy after intradermal immunization

“…Moreover, GAP immunized IFNc) ⁄ ) mice produced sporozoite-specific antibodies but were not protected against a WT challenge (34). Overall, our findings corroborate the conclusions of a meta-analysis by Guilbride et al (35), emphasizing the poor capacity to induce protective efficacy after sporozoite inoculation via the skin as compared to the IV route. Although in human volunteers whole parasite immunization by bite of infected mosquitoes can induce complete protection (6,(36)(37)(38), mosquito bites are obviously not a practical route of immunization.…”

“…Overall, our findings corroborate the conclusions of a meta‐analysis by Guilbride et al. (35), emphasizing the poor capacity to induce protective efficacy after sporozoite inoculation via the skin as compared to the IV route.…”

Reduced Plasmodium berghei sporozoite liver load associates with low protective efficacy after intradermal immunization

“…Moreover, GAP immunized IFNγ -/-mice produced sporozoite-specific antibodies but were not protected against a WT challenge (34). Overall, our findings corroborate the conclusions of a meta-analysis by Guilbride et al, emphasizing the poor capacity to induce protective efficacy after sporozoite inoculation via the skin as compared to the IV route (35).…”

Vaccination with Plasmodium knowlesi AMA1 Formulated in the Novel Adjuvant Co-Vaccine HT™ Protects against Blood-Stage Challenge in Rhesus Macaques

“…10,000) iRBC. It is possible that sporozoite passage through the skin may have induced tolerance as was recently hypothesised [44]. Thus the route of infection and initial infection load may, in part, explain the differences.…”

Reduced Plasmodium berghei sporozoite liver load associates with low protective efficacy after intradermal immunization

“…Moreover, GAP immunized IFNc) ⁄ ) mice produced sporozoite-specific antibodies but were not protected against a WT challenge (34). Overall, our findings corroborate the conclusions of a meta-analysis by Guilbride et al (35), emphasizing the poor capacity to induce protective efficacy after sporozoite inoculation via the skin as compared to the IV route. Although in human volunteers whole parasite immunization by bite of infected mosquitoes can induce complete protection (6,(36)(37)(38), mosquito bites are obviously not a practical route of immunization.…”

“…Overall, our findings corroborate the conclusions of a meta‐analysis by Guilbride et al. (35), emphasizing the poor capacity to induce protective efficacy after sporozoite inoculation via the skin as compared to the IV route.…”

Reduced Plasmodium berghei sporozoite liver load associates with low protective efficacy after intradermal immunization

“…Moreover, GAP immunized IFNγ -/-mice produced sporozoite-specific antibodies but were not protected against a WT challenge (34). Overall, our findings corroborate the conclusions of a meta-analysis by Guilbride et al, emphasizing the poor capacity to induce protective efficacy after sporozoite inoculation via the skin as compared to the IV route (35).…”

Vaccination with Plasmodium knowlesi AMA1 Formulated in the Novel Adjuvant Co-Vaccine HT™ Protects against Blood-Stage Challenge in Rhesus Macaques

“…10,000) iRBC. It is possible that sporozoite passage through the skin may have induced tolerance as was recently hypothesised [44]. Thus the route of infection and initial infection load may, in part, explain the differences.…”

Reduced Plasmodium berghei sporozoite liver load associates with low protective efficacy after intradermal immunization

“…Moreover, GAP immunized IFNc) ⁄ ) mice produced sporozoite-specific antibodies but were not protected against a WT challenge (34). Overall, our findings corroborate the conclusions of a meta-analysis by Guilbride et al (35), emphasizing the poor capacity to induce protective efficacy after sporozoite inoculation via the skin as compared to the IV route. Although in human volunteers whole parasite immunization by bite of infected mosquitoes can induce complete protection (6,(36)(37)(38), mosquito bites are obviously not a practical route of immunization.…”

“…Overall, our findings corroborate the conclusions of a meta‐analysis by Guilbride et al. (35), emphasizing the poor capacity to induce protective efficacy after sporozoite inoculation via the skin as compared to the IV route.…”

Reduced Plasmodium berghei sporozoite liver load associates with low protective efficacy after intradermal immunization

“…Moreover, GAP immunized IFNγ -/-mice produced sporozoite-specific antibodies but were not protected against a WT challenge (34). Overall, our findings corroborate the conclusions of a meta-analysis by Guilbride et al, emphasizing the poor capacity to induce protective efficacy after sporozoite inoculation via the skin as compared to the IV route (35).…”

Vaccination with Plasmodium knowlesi AMA1 Formulated in the Novel Adjuvant Co-Vaccine HT™ Protects against Blood-Stage Challenge in Rhesus Macaques

“…10,000) iRBC. It is possible that sporozoite passage through the skin may have induced tolerance as was recently hypothesised [44]. Thus the route of infection and initial infection load may, in part, explain the differences.…”