Comparative assessment of vaccine vectors encoding ten malaria antigens identifies two protective liver-stage candidates.

Rhea J Longley,Chris J Janse,Ahmed M Salman,Matthew G Cottingham,Alexandra J Spencer,Adrian V S Hill,Katie Ewer,Shahid M Khan

doi:10.1038/srep11820

Abstract

The development of an efficacious Plasmodium falciparum malaria vaccine remains a top priority for global health. Vaccination with irradiated sporozoites is able to provide complete sterile protection through the action of CD8+ T cells at the liver-stage of infection. However, this method is currently unsuitable for large-scale deployment and focus has instead turned to the development of sub-unit vaccines. Sub-unit vaccine efforts have traditionally focused on two well-known pre-erythrocytic antigens, CSP and TRAP, yet thousands of genes are expressed in the liver-stage. We sought to assess the ability of eight alternative P. falciparum pre-erythrocytic antigens to induce a high proportion of CD8+ T cells. We show that all antigens, when expressed individually in the non-replicating viral vectors ChAd63 and MVA, are capable of inducing an immune response in mice. Furthermore, we also developed chimeric P. berghei parasites expressing the cognate P. falciparum antigen to enable assessment of efficacy in mice. Our preliminary results indicate that vectors encoding either PfLSA1 or PfLSAP2 are capable of inducing sterile protection dependent on the presence of CD8+ T cells. This work has identified two promising P. falciparum liver-stage candidate antigens that will now undergo further testing in humans.

Highlights

Sub-unit vaccination strategy is the induction of high numbers of CD8+ T cells to kill infected hepatocytes
The pre-erythrocytic sub-unit vaccines currently undergoing clinical assessment are based on only two antigens, namely PfCSP and PfTRAP
Our results demonstrate that other antigen candidates are capable of inducing strong CD8+ T cell responses and may be better targets for a liver-stage malaria vaccine

Summary

Introduction

Sub-unit vaccination strategy is the induction of high numbers of CD8+ T cells to kill infected hepatocytes. The ME-TRAP vaccine combines the pre-erythrocytic antigen thrombospondin-related adhesion protein (TRAP) with a multi-epitope string (ME) and is delivered via the viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA)[7]. Whilst this vaccine displays moderate levels of efficacy in naïve-adults, it induces exceptionally high CD8+ T cell responses. Rodent malaria parasite species are routinely used for proof-of-concept studies, yet several newly identified P. falciparum antigen candidates do not have orthologs in murine malaria parasite species Another strategy to study P. falciparum immunology and assess malaria vaccines has been the generation of transgenic rodent malaria parasites expressing P. falciparum proteins[12]. We report the successful production of eight vaccines inducing strong CD8+ T cell responses and preliminary results demonstrating superior efficacy of ChAd63-MVA prime-boost vaccines encoding one of two antigens, P. falciparum (Pf) liver-stage antigen 1 (LSA1) or liver-stage associated protein 2 (LSAP2), when compared to both PfCSP and PfTRAP

Methods

Results

Conclusion