Chemically attenuated blood-stage Plasmodium yoelii parasites induce long-lived and strain-transcending protection

The development of a vaccine is essential for the elimination of malaria. However, despite many years of effort, a successful vaccinehas not been achieved. Most subunit vaccine candidates tested in clinical trials have provided limited efficacy, and thus attenuatedwhole-parasite vaccines are now receiving close scrutiny. Here, we test chemically attenuated Plasmodium yoelii 17Xand demonstrate significant protection following homologous and heterologous blood-stage challenge. Protection againstblood-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 toloss of vaccine-induced protection. In spite of significant activation of circulating CD8⁺ T cells, liver-stage immunity was notevident. 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 providescritical insight into whole-parasite vaccine-induced immunity and strong support for testing whole-parasite vaccines in humans.