Seattle Biomedical Research Institute

Ruprecht-karls-universitat Heidelberg

Seattle Children's Hospital

US Government As Represented by the Secretary of the Army

Walter and Eliza Hall Institute of Medical Research

Philadelphia Health and Education Corporation

Stefan H I Kappe

Ann-Kristin Mueller

Kai-Uwe C Matuschewski

Ashley M Vaughan

Dorender A Dankwa

Patrick Emmet Duffy

Alan E Cowman

Igor Bacik

Lawrence W Bergman

Jason P Wendler

Donald G Heppner

Vladislav A Malkov

Alexander Gerd Maier

Urszula Krzych

Alice Tarun

Kelley Van Buskirk

Mehdi Labaied

Ahmed Sayed Ibrahim Aly

The disclosure relates to doubly attenuated malaria parasites that have had the functionality of LISP2 and PlasMei2 genes interrupted through genetic manipulation. The double attenuated malaria parasites disclosed herein are useful for methods and compositions for stimulating of vertebrate host immune systems because of the complete cessation of lifecycle progression in the late liver stage, while providing a comprehensive antigenic presentation representing wildtype liver stage parasites. The disclosure also relates to the additional blood stage and gametocyte antigens to compositions of genetically attenuated malaria parasites (GAPs) to enhance efficient immune stimulation and prevention of disease and transmission related to the presence of blood stage parasites.

Doubly attenuated late liver stage malaria parasites and related compositions and methods

The disclosure relates to doubly attenuated malaria parasites that have had the functionality of LISP 2 and PlasMei2 genes interrupted through genetic manipulation. The double attenuated malaria parasites disclosed herein are useful for methods and compositions for stimulating of vertebrate host immune systems because of the complete cessation of lifecycle progression in the late liver stage, while providing a comprehensive antigenic presentation representing wildtype liver stage parasites. The disclosure also relates to the additional blood stage and gametocyte antigens to compositions of genetically attenuated malaria parasites (GAPs) to enhance efficient immune stimulation and prevention of disease and transmission related to the presence of blood stage parasites.

The invention provides isolated liver stagepolypeptides comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:1-48 and immunogenic derivatives thereof. The invention also provides isolated nucleic acid molecules encoding the liver stagepolypeptides of the invention, compositions comprising one or more liver stagepolypeptides of the invention, methods for inducing an immune response against the liver stagepolypeptides, and methods for treating and diagnosing liver stage malaria.

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Method for inoculating a vertebrate host against malaria, by administering to the host a liveorganism that is genetically engineered to disrupt a liver-stage-specific gene function.

Live genetically attenuated malaria vaccine

The invention provides methods for inducing an immune response in a vertebrate host against a protozoan parasite, comprising administering to the host a live protozoan parasite that is genetically engineered to disrupt a stage-specific gene function that is required by the protozoan parasite to establish a secondary infection in the vertebrate host. Representative protozoan parasites belong to the phyla Apicomplexa and Kinetoplastida. The vertebrate host may be a mammal or a bird.

Live genetically engineered protozoan vaccine

Method for inoculating a vertebrate host against malaria, by administering to the host a liveorganism that is genetically engineered to disrupt a gene whose expression is up-regulated in liver stage parasites and whose function is not required for entry into hose hepatocytes.

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Seattle, WA, United States of America

Stefan H I Kappe