Human CD8+ T cells mediate protective immunity induced by a human malaria vaccine in human immune system mice

Abstract

A number of studies have shown that CD8+ T cells mediate protective anti-malaria immunity in a mouse model. However, whether human CD8+ T cells play a role in protection against malaria remains unknown. We recently established human immune system (HIS) mice harboring functional human CD8+ T cells (HIS-CD8 mice) by transduction with HLA-A∗0201 and certain human cytokines using recombinant adeno-associated virus-based gene transfer technologies. These HIS-CD8 mice mount a potent, antigen-specific HLA-A∗0201-restricted human CD8+ T-cell response upon immunization with a recombinant adenovirus expressing a human malaria antigen, the Plasmodium falciparum circumsporozoite protein (PfCSP), termed AdPfCSP. In the present study, we challenged AdPfCSP-immunized HIS-CD8 mice with transgenic Plasmodium berghei sporozoites expressing full-length PfCSP and found that AdPfCSP-immunized (but not naïve) mice were protected against subsequent malaria challenge. The level of the HLA-A∗0201-restricted, PfCSP-specific human CD8+ T-cell response was closely correlated with the level of malaria protection. Furthermore, depletion of human CD8+ T cells from AdPfCSP-immunized HIS-CD8 mice almost completely abolished the anti-malaria immune response. Taken together, our data show that human CD8+ T cells mediate protective anti-malaria immunity in vivo.

A potent malaria vaccine based on adenovirus with dual modifications at Hexon and pVII

“…Apart from a conventional mouse model, we have most recently been able to show that a single immunizing dose of AdPfCSP induced anti-malaria immunity in humanized mice that mimic human immune system [41] and that the protective anti-malaria immunity was abolished by the depletion of human CD8+ T cells in vivo , indicating the protective role of human CD8+ T cells against malaria [42]. Retrospective analysis of immune responses in RTS,S clinical trials revealed that CSP-specific CD4+ T cell response is an independent factor associated with protection [18], thus suggesting the protective role of human CD4+ T cells against malaria.…”

A potent adjuvant effect of a CD1d-binding NKT cell ligand in human immune system mice

“…Human fetal liver samples were obtained via a non-profit partner (Advanced Bioscience Resources, Alameda, CA); the samples were devoid of any information that would identify the subjects from whom they were derived. Therefore, IRB approval was not required for their use, as previously described [22, 24]. …”

“…The sporozoite challenge experiment was conducted as described previously [24]. Briefly, a group of HIS-A2/hCD1d humanized mice were immunized with 2 × 10 5 radiation-attenuated PfCSP/Py Spz, and 10 days later, groups of immunized as well as naïve HIS-A2/hCD2d mice were challenged with 2 × 10 4 live PfCSP/Py Spz by IV injection.…”

“…Briefly, a group of HIS-A2/hCD1d humanized mice were immunized with 2 × 10 5 radiation-attenuated PfCSP/Py Spz, and 10 days later, groups of immunized as well as naïve HIS-A2/hCD2d mice were challenged with 2 × 10 4 live PfCSP/Py Spz by IV injection. Forty-two hours later, livers were collected from both groups of challenged HIS-A2/hCD1d mice, and the amount of parasite-specific ribosomal RNA was determined by using a 7300 Real-Time PCR System (Applied Biosystems), as described previously [24]. Parasite burden was calculated as a ratio of the absolute copy number of parasite ribosomal RNA to that of mouse GAPDH mRNA.…”

“…In view of a previous study showing that human CD4 molecules can weakly interact with murine class II molecules [23], it is possible that some of human CD4+ T cells in HIS-A2 mice may be functional. Nevertheless, we have most recently shown that in vivo depletion of human CD8+ T cells almost completely abolished the protective anti-malaria immunity induced in HIS-A2 mice immunized with a recombinant adenovirus expressing the Plasmodium falciparum circumsporozoite protein (AdPfCSP) [24]. …”