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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

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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 3

Immune responses induced by chemically attenuated parasites.

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Immune responses induced by chemically attenuated parasites.
(A) C57BL/6...
(A) C57BL/6 mice (12 per group) were vaccinated with 106P. chabaudi prbcs attenuated with centanamycin or injected with saline. Phenotypes of blood CD4+ and CD8+ cells were assessed on days 5 and 21 after vaccination. Values for means of the saline group were subtracted from values for each vaccinated mouse. Each circle represents 1 mouse. Horizontal bars represent means. One sample t test was performed comparing values to the saline mean of zero. (B) Three A/J mice were immunized with 3 doses of vaccine (each, 106 centanamycin-attenuated P. chabaudi prbcs), and spleen cells from these and a naive mouse were collected 8 weeks after the last immunization and cultured with indicated antigens; uptake of 3H thymidine was determined after 72 hours as described in Methods. (C) C57BL/6 mice (5 per group) were vaccinated with 106P. chabaudi prbcs or equivalent nrbcs attenuated with centanamycin and sacrificed on day 5. Spleen cells were stimulated in vitro for 4 hours with PMA and ionomycin in the presence of BFA and stained for IFN-γ. Percentage that was IFN-γ positive was determined by subtracting isotype control and values from mice injected with saline for CD4 and CD8 populations. (D) Three A/J mice were immunized with 3 doses of vaccine (each, 106 centanamycin-attenuated P. chabaudi prbcs), and spleen cells from these mice were collected 50 days after the last immunization, cultured with indicated antigens, and after 72 hours culture, supernatants collected and use for cytokine bead analysis as described in Methods. (E) C57BL/6 mice (CD45.2, 5 per group) were adoptively transferred with OT-II T cells (CD45.1), and 1 group received ovalbumin peptide 323–339 mixed with LPS i.p. 24 hours later, mice were immunized i.v. with 106P. chabaudi prbcs or equivalent nrbcs attenuated with centanamycin. Mice were bled on day 6 after immunization and the phenotype of donor and recipient cells determined by flow cytometry. Percentages were calculated by subtracting values from mice receiving OT-II cells alone.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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