Chemically Attenuated Blood-Stage Plasmodium yoelii Parasites Induce Long-Lived and Strain-Transcending Protection.

Amber I Raja,Danielle I Stanisic,Virginia Mcphun,Stephen L Hoffman,Denise L Doolan,Yeping Cai,Penny Groves,Jennifer M Reiman,Ian Cockburn,Sumana Chakravarty,Michael F Good

doi:10.1128/iai.00157-16

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.

Highlights

Malaria is a major global health burden, with nearly half of the human population at risk of becoming infected with Plasmodium parasites [1]
We investigated the protective efficacy of chemically attenuated P. yoelii blood-stage parasites
Investigations into the cellular immune responses induced by vaccination with chemically attenuated P. yoelii 17X showed activated circulating CD8ϩ T cells but only limited activation of circulating CD4ϩ T cells

Summary

Introduction

Malaria is a major global health burden, with nearly half of the human population at risk of becoming infected with Plasmodium parasites [1]. The development of malaria vaccines has largely focused on a limited number of recombinant subunit vaccine candidates, immune responses to which have shown an association with protection in immunoepidemiological studies [2,3,4]. Vaccination with chemically attenuated synchronous Plasmodium chabaudi ring-stage parasites was shown to protect mice against parasite challenge [20] These results are encouraging, they do not indicate that attenuated whole bloodstage parasites will provide a general strategy for vaccine development, in particular for parasites where cellular tropism and sequestration differ and where different mechanisms of immunity are known to be relevant. In some parasite species, the activation of cellular immune responses was shown to be associated with the induction of pathology [24] These various observations indicate the need for further preclinical investigations of the attenuated blood-stage malaria vaccine strategy

Methods

Results

Conclusion