Mechanisms of Stage-Transcending Protection Following Immunization of Mice with Late Liver Stage-Arresting Genetically Attenuated Malaria Parasites

Brandon Wilder, Gladys J. Keitany, Ashley M. Vaughan, Jessica L. Miller, Ruobing Wang, Stefan H.I. Kappe

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Malaria, caused by Plasmodium parasite infection, continues to be one of the leading causes of worldwide morbidity and mortality. Development of an effective vaccine has been encumbered by the complex life cycle of the parasite that has distinct pre-erythrocytic and erythrocytic stages of infection in the mammalian host. Historically, malaria vaccine development efforts have targeted each stage in isolation. An ideal vaccine, however, would target multiple life cycle stages with multiple arms of the immune system and be capable of eliminating initial infection in the liver, the subsequent blood stage infection, and would prevent further parasite transmission. We have previously shown that immunization of mice with Plasmodium yoelii genetically attenuated parasites (GAP) that arrest late in liver stage development elicits stage-transcending protection against both a sporozoite challenge and a direct blood stage challenge. Here, we show that this immunization strategy engenders both T- and B-cell responses that are essential for stage-transcending protection, but the relative importance of each is determined by the host genetic background. Furthermore, potent anti-blood stage antibodies elicited after GAP immunization rely heavily on FC-mediated functions including complement fixation and FC receptor binding. These protective antibodies recognize the merozoite surface but do not appear to recognize the immunodominant merozoite surface protein-1. The antigen(s) targeted by stage-transcending immunity are present in both the late liver stages and blood stage parasites. The data clearly show that GAP-engendered protective immune responses can target shared antigens of pre-erythrocytic and erythrocytic parasite life cycle stages. As such, this model constitutes a powerful tool to identify novel, protective and stage-transcending T and B cell targets for incorporation into a multi-stage subunit vaccine.

Original languageEnglish (US)
Article numbere1004855
JournalPLoS pathogens
Volume11
Issue number5
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Malaria
Immunization
Parasites
Liver
Life Cycle Stages
B-Lymphocytes
Vaccines
Infection
Merozoite Surface Protein 1
Plasmodium yoelii
Malaria Vaccines
Merozoites
Antigens
Sporozoites
Parasitic Diseases
Subunit Vaccines
Antibodies
Transcend
Immune System
Immunity

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Mechanisms of Stage-Transcending Protection Following Immunization of Mice with Late Liver Stage-Arresting Genetically Attenuated Malaria Parasites. / Wilder, Brandon; Keitany, Gladys J.; Vaughan, Ashley M.; Miller, Jessica L.; Wang, Ruobing; Kappe, Stefan H.I.

In: PLoS pathogens, Vol. 11, No. 5, e1004855, 01.01.2015.

Research output: Contribution to journalArticle

Wilder, Brandon ; Keitany, Gladys J. ; Vaughan, Ashley M. ; Miller, Jessica L. ; Wang, Ruobing ; Kappe, Stefan H.I. / Mechanisms of Stage-Transcending Protection Following Immunization of Mice with Late Liver Stage-Arresting Genetically Attenuated Malaria Parasites. In: PLoS pathogens. 2015 ; Vol. 11, No. 5.
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