Progress with viral vectored malaria vaccines: A multi-stage approach involving “unnatural immunity”

Abstract

Viral vectors used in heterologous prime-boost regimens are one of very few vaccination approaches that have yielded significant protection against controlled human malaria infections. Recently, protection induced by chimpanzee adenovirus priming and modified vaccinia Ankara boosting using the ME-TRAP insert has been correlated with the induction of potent CD8+ T cell responses. This regimen has progressed to field studies where efficacy against infection has now been reported. The same vectors have been used pre-clinically to identify preferred protective antigens for use in vaccines against the pre-erythrocytic, blood-stage and mosquito stages of malaria and this work is reviewed here for the first time. Such antigen screening has led to the prioritization of the PfRH5 blood-stage antigen, which showed efficacy against heterologous strain challenge in non-human primates, and vectors encoding this antigen are in clinical trials. This, along with the high transmission-blocking activity of some sexual-stage antigens, illustrates well the capacity of such vectors to induce high titre protective antibodies in addition to potent T cell responses. All of the protective responses induced by these vectors exceed the levels of the same immune responses induced by natural exposure supporting the view that, for subunit vaccines to achieve even partial efficacy in humans, “unnatural immunity” comprising immune responses of very high magnitude will need to be induced.

Endosomophagy clears disrupted early endosomes but not virus particles during virus entry into cells     

“…Notably, in spite of the robust cross-reacting cellular and humoral immune responses against HAdV infections, latent or persistent adenovirus infections in humans occur, and may last for years [60]. The report here also impinges on gene therapy and vaccination protocols, considering the prominent roles of adenoviruses in clinical gene therapy, and as vaccination adjuvants [61]. Follow-up analyses of this observation can be directed to the identification of host and viral targets for ubiquitin ligases and deubiquitinases, host adaptor proteins, or the role of virus-induced sphingolipids in tuning endosomophagy [34].…”

Plasmodium falciparum pre-erythrocytic stage vaccine development

“…Several viral [96][97][98][99][100], bacterial [101][102][103][104] and parasite [105][106][107] vectors have been used in anti-malarial vaccine candidates; currently, many clinical trials are exploring their advantages to increase their potential and accelerate their use in vaccines [11,108].…”

The use of transgenic parasites in malaria vaccine research

“…Transgenic Plasmodium parasites expressing OVA have been exploited to examine parasitespecific CD8 + T cell responses during both blood and liver PfUIS3/ PfTRAP PF3D7_1302200 PF3D7_1335900 (2) Additional copies; Pf (NF54) genes under the control of Pbuis4 promoter; in Pb (ANKA) #4076 [32] PfCSP/ PfTRAP PF3D7_0304600 PF3D7_1335900 (2) Additional copies; Pf (NF54) genes under the control of Pbuis4 promoter; inPb (ANKA) [33] PfCSP PF3D7_0304600 Replacement copy; Pb (ANKA)csp replaced by Pf(Wellcome strain) csp, full-length Pbcsp promoter & 302bp Pbcsp3ʹUTR.…”