Cross-species malaria immunity induced by chemically attenuated parasites
Michael F. Good, … , Moses Lee, Virginia McPhun
Michael F. Good, … , Moses Lee, Virginia McPhun
Published July 1, 2013
Citation Information: J Clin Invest. 2013;123(8):3353-3362. https://doi.org/10.1172/JCI66634.
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Research Article Infectious disease

Cross-species malaria immunity induced by chemically attenuated parasites

Abstract

Vaccine development for the blood stages of malaria has focused on the induction of antibodies to parasite surface antigens, most of which are highly polymorphic. An alternate strategy has evolved from observations that low-density infections can induce antibody-independent immunity to different strains. To test this strategy, we treated parasitized red blood cells from the rodent parasite Plasmodium chabaudi with seco-cyclopropyl pyrrolo indole analogs. These drugs irreversibly alkylate parasite DNA, blocking their ability to replicate. After administration in mice, DNA from the vaccine could be detected in the blood for over 110 days and a single vaccination induced profound immunity to different malaria parasite species. Immunity was mediated by CD4+ T cells and was dependent on the red blood cell membrane remaining intact. The human parasite, Plasmodium falciparum, could also be attenuated by treatment with seco-cyclopropyl pyrrolo indole analogs. These data demonstrate that vaccination with chemically attenuated parasites induces protective immunity and provide a compelling rationale for testing a blood-stage parasite-based vaccine targeting human Plasmodium species.

Authors

Michael F. Good, Jennifer M. Reiman, I. Bibiana Rodriguez, Koichi Ito, Stephanie K. Yanow, Ibrahim M. El-Deeb, Michael R. Batzloff, Danielle I. Stanisic, Christian Engwerda, Terry Spithill, Stephen L. Hoffman, Moses Lee, Virginia McPhun

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Figure 4

Vaccine protection requires an intact rbc membrane.

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Vaccine protection requires an intact rbc membrane. The role of the sple...
The role of the spleen early (5 weeks) after vaccination. (A) To determine whether the rbc membrane must remain intact for vaccine efficacy, cohorts of 5 A/J mice were vaccinated with a single dose of 106P. chabaudi prbcs attenuated with centanamycin or a vaccine lysed with distilled water, then returned to isotonicity with 2× PBS. Naive mice served as a control. Five weeks later, mice were challenged with 105P. chabaudi prbcs i.v. and parasitemia monitored. Plus signs indicate that mice succumbed to the infection. (B) To determine the importance of the spleen to immunity early after vaccination, A/J mice were splenectomized and others had a sham splenectomy. Four weeks later, half were immunized i.v. with 3 doses of 106P. chabaudi prbcs attenuated by treatment with centanamycin, each 2 weeks apart. The other half received no treatment. Five weeks after the final dose of vaccine, all mice were challenged with 105 prbcs i.v. and parasitemia monitored. Plus signs indicate that mice succumbed to the infection.