Humanized DRAGA mice immunized with Plasmodium falciparum sporozoites and chloroquine elicit protective pre-erythrocytic immunity

Sai Majji,Soumya Shashikumar,Wathsala Wijayalath,Sofia Casares,Teodor D Brumeanu

doi:10.1186/s12936-018-2264-y

Abstract

BackgroundHuman-immune-system humanized mouse models can bridge the gap between humans and conventional mice for testing human vaccines. The HLA-expressing humanized DRAGA (HLA-A2.HLA-DR4.Rag1KO.IL2RγcKO.NOD) mice reconstitute a functional human-immune-system and sustain the complete life cycle of Plasmodium falciparum. Herein, the DRAGA mice were investigated for immune responses following immunization with live P. falciparum sporozoites under chloroquine chemoprophylaxis (CPS-CQ), an immunization approach that showed in human trials to confer pre-erythrocytic immunity.ResultsThe CPS-CQ immunized DRAGA mice (i) elicited human CD4 and CD8 T cell responses to antigens expressed by P. falciparum sporozoites (Pfspz) and by the infected-red blood cells (iRBC). The Pfspz-specific human T cell responses were found to be systemic (spleen and liver), whereas the iRBCs-specific human T cell responses were more localized to the liver, (ii) elicited stronger antibody responses to the Pfspz than to the iRBCs, and (iii) they were protected against challenge with infectious Pfspz but not against challenge with iRBCs.ConclusionsThe DRAGA mice represent a new pre-clinical model to investigate the immunogenicity and protective efficacy of P. falciparum malaria vaccine candidates.

Highlights

Human-immune-system humanized mouse models can bridge the gap between humans and conventional mice for testing human vaccines
The results indicate the potential of DRAGA mice to investigate the immunogenicity and protective efficacy of P. falciparum malaria vaccine candidates
This study showed that DRAGA mice immunized with P. falciparum CPS-CQ elicited human T cell and antibody responses and they were protected against malaria

Summary

Introduction

Human-immune-system humanized mouse models can bridge the gap between humans and conventional mice for testing human vaccines. IL2RγcKO.NOD) mice reconstitute a functional human-immune-system and sustain the complete life cycle of Plasmodium falciparum. The DRAGA mice were investigated for immune responses following immunization with live P. falciparum sporozoites under chloroquine chemoprophylaxis (CPS-CQ), an immunization approach that showed in human trials to confer pre-erythrocytic immunity. Mature liver stage parasites are released to the bloodstream to invade the red blood cells and to initiate the asexual erythrocytic cycles responsible for the clinical. New World monkeys, and chimpanzees have been used for decades as pre-clinical models of malaria. The duration of liver stage infection is 2–3 days for rodent malaria parasites, but 7 days for P. falciparum [3]. Rodent malaria parasites lack orthologues for many proteins expressed by P. falciparum

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