Raja, Amber I., Cai, Yeping, Reiman, Jennifer M., Groves, Penny, Chakravarty, Sumana, McPhun, Virginia, Doolan, Denise L., Cockburn, Ian, Hoffman, Stephen L., Stanisic, Danielle I., and Good, Michael F. (2016) Chemically attenuated blood-stage Plasmodium yoelii parasites induce long-lived and strain-transcending protection. Infection and Immunity, 84 (8). pp. 2274-2288.

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Abstract

The development of a vaccine is essential for the elimination of malaria. However, despite many years of effort, a successful vaccine has not been achieved. Most subunit vaccine candidates tested in clinical trials have provided limited efficacy, and thus attenuated whole-parasite vaccines are now receiving close scrutiny. Here, we test chemically attenuated Plasmodium yoelii 17X and demonstrate significant protection following homologous and heterologous blood-stage challenge. Protection against blood-stage infection persisted for at least 9 months. Activation of both CD4+ and CD8+ T cells was shown after vaccination; however, in vivo studies demonstrated a pivotal role for both CD4+ T cells and B cells since the absence of either cell type led to loss of vaccine-induced protection. In spite of significant activation of circulating CD8+ T cells, liver-stage immunity was not evident. Neither did vaccine-induced CD8+ T cells contribute to blood-stage protection; rather, these cells contributed to pathogenesis, since all vaccinated mice depleted of both CD4+ and CD8+ T cells survived a challenge infection. This study provides critical insight into whole-parasite vaccine-induced immunity and strong support for testing whole-parasite vaccines in humans.

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