Translating the Immunogenicity of Prime-boost Immunization With ChAd63 and MVA ME-TRAP From Malaria Naive to Malaria-endemic Populations

Abstract

To induce a deployable level of efficacy, a successful malaria vaccine would likely benefit from both potent cellular and humoral immunity. These requirements are met by a heterologous prime-boost immunization strategy employing a chimpanzee adenovirus vector followed by modified vaccinia Ankara (MVA), both encoding the pre-erythrocytic malaria antigen ME-thrombospondin-related adhesive protein (TRAP), with high immunogenicity and significant efficacy in UK adults. We undertook two phase 1b open-label studies in adults in Kenya and The Gambia in areas of similar seasonal malaria transmission dynamics and have previously reported safety and basic immunogenicity data. We now report flow cytometry and additional interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) data characterizing pre-existing and induced cellular immunity as well as anti-TRAP IgG responses. T-cell responses induced by vaccination averaged 1,254 spot-forming cells (SFC) per million peripheral blood mononuclear cells (PBMC) across both trials and flow cytometry revealed cytokine production from both CD4(+) and CD8(+) T cells with the frequency of CD8(+) IFN-γ-secreting monofunctional T cells (previously shown to associate with vaccine efficacy) particularly high in Kenyan adults. Immunization with ChAd63 and MVA ME-TRAP induced strong cellular and humoral immune responses in adults living in two malaria-endemic regions of Africa. This prime-boost approach targeting the pre-erythrocytic stage of the malaria life-cycle is now being assessed for efficacy in a target population.

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

“…Reactogenicity of the ChAd63 RH5 vector was similar to that seen with the same doses of ChAd63 vectored vaccines encoding the P. falciparum antigen multiepitope string-thrombospondin-related adhesion protein (ME-TRAP), circumsporozoite protein (CSP), MSP1, or AMA1 (36-39, 52, 54) or the P. vivax antigen Duffy-binding protein region II (PvDBP_RII) (43). The same vectors encoding ME-TRAP have similarly been safe following immunization of adults, children, and infants residing in malaria-endemic areas (41,42). Our data with ChAd63 RH5 add to the growing body of evidence that this simian adenovirus vector is safe for clinical use.…”

“…This heterologous prime-boost approach has shown antibody induction against difficult-to-express malaria antigens in numerous animal models, including nonhuman primates (32,34,35). These vectors, delivering antigens from P. falciparum, have now been shown to be safe and immunogenic for T cell and antibodies in healthy European and American adult volunteers (36)(37)(38)(39)(40), as well as African adults, children, and infants (41,42). More recently, similar adenovirus-poxvirus vectored vaccine technologies have been used to immunize humans against numerous other pathogens including P. vivax malaria (43), Ebola virus (44), hepatitis C virus (HCV) (45), respiratory syncytial virus (RSV) (46) and HIV-1 (47).…”

Recent Developments in Malaria Vaccinology

“…In 2013, the ChAd63-MVA ME-TRAP alone vaccine was tested in a Phase Ib dose escalation study in healthy Gambian and Kenyan adults (Kimani et al, 2014;Ogwang et al, 2013). The encouraging immunogenicity data of the Phase I/IIa studies in UK malaria-naïve volunteers was again confirmed.…”

Antiparasitic DNA vaccines in 21st century

“…The DNA prime/vector boost concept, has been initialy used mostly in research on vaccine against malaria (Schneider et al 2001;Kimani et al 2014). DNA priming appears to improve the outcome of boosting with recombinant proteins, or with vector-based vaccines.…”