Adenovirus-prime and baculovirus-boost heterologous immunization achieves sterile protection against malaria sporozoite challenge in a murine model

Kunitaka Yoshida,Katarzyna A Sala,Masaharu Tokoro,Mitsuhiro Iyori,Daisuke S Yamamoto,Shahid M Khan,Pawan Dulal,Tatsuya Yoshii,Shigeto Yoshida,Andrew M Blagborough,Yenni Yusuf,Pawan Dulal,Chris J Janse,Adrian V S Hill,Adrian V S Hill,Sumi Biswas,Sumi Biswas,Ahmed M Salman,Ahmed M Salman,Ahmed M Salman

doi:10.1038/s41598-018-21369-y

Abstract

With the increasing prevalence of artemisinin-resistant malaria parasites, a highly efficacious and durable vaccine for malaria is urgently required. We have developed an experimental virus-vectored vaccine platform based on an envelope-modified baculovirus dual-expression system (emBDES). Here, we show a conceptually new vaccine platform based on an adenovirus-prime/emBDES-boost heterologous immunization regimen expressing the Plasmodium falciparum circumsporozoite protein (PfCSP). A human adenovirus 5-prime/emBDES-boost heterologous immunization regimen consistently achieved higher sterile protection against transgenic P. berghei sporozoites expressing PfCSP after a mosquito-bite challenge than reverse-ordered or homologous immunization. This high protective efficacy was also achieved with a chimpanzee adenovirus 63-prime/emBDES-boost heterologous immunization regimen against an intravenous sporozoite challenge. Thus, we show that the adenovirus-prime/emBDES-boost heterologous immunization regimen confers sterile protection against sporozoite challenge by two individual routes, providing a promising new malaria vaccine platform for future clinical use.

Highlights

Malaria remains a severe public health problem and causes significant economic losses worldwide
We have shown that baculovirus dual-expression system’ (BDES) is an effective malaria vaccine platform for all three stages of the Plasmodium life cycle, including the pre-erythrocytic stage[8,9,10], asexual blood stage[11,12], and sexual stage[9,13,14,15], when transgenic P. berghei parasites expressing human Plasmodium antigens were used for its evaluation
We have previously shown that envelope-modified baculovirus dual-expression system (emBDES)-P. falciparum circumsporozoite protein (PfCSP)/IL12 requires 3–4 doses of immunization to elicit 60–80% sterile protection against sporozoite challenge[17]

Summary

Introduction

Malaria remains a severe public health problem and causes significant economic losses worldwide. Several studies have shown the efficacy of heterologous prime-boost immunization strategies in inducing T-cell-mediated immunity against a variety of pathogens, including Mycobacterium tuberculosis[18,19,20,21,22,23], human immunodeficiency virus[24,25], and Ebola virus[26,27]. Researchers in malaria at the Jenner Institute (University of Oxford, Oxford, UK) have demonstrated that a heterologous prime-boost immunization regimen using a replication-deficient chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) increased the number of antigen-specific CD8+ T cells, improving the protective efficacy in mouse and macaque models[28,29,30]. It is widely recognized that a successful pre-erythrocytic malaria vaccine must induce humoral immune responses and CD8+ T-cell-mediated immune responses[31,32,33,34,35] to inhibit the infection of the liver by sporozoites and to eliminate any resulting liver-stage parasites that develop in hepatocytes

Methods

Results

Conclusion