A Glycolipid Adjuvant, 7DW8-5, Enhances CD8+ T Cell Responses Induced by an Adenovirus-Vectored Malaria Vaccine in Non-Human Primates

Abstract

A key strategy to a successful vaccine against malaria is to identify and develop new adjuvants that can enhance T-cell responses and improve protective immunity. Upon co-administration with a rodent malaria vaccine in mice, 7DW8-5, a recently identified novel analog of α-galactosylceramide (α-GalCer), enhances the level of malaria-specific protective immune responses more strongly than the parent compound. In this study, we sought to determine whether 7DW8-5 could provide a similar potent adjuvant effect on a candidate human malaria vaccine in the more relevant non-human primate (NHP) model, prior to committing to clinical development. The candidate human malaria vaccine, AdPfCA (NMRC-M3V-Ad-PfCA), consists of two non-replicating recombinant adenoviral (Ad) vectors, one expressing the circumsporozoite protein (CSP) and another expressing the apical membrane antigen-1 (AMA1) of Plasmodium falciparum. In several phase 1 clinical trials, AdPfCA was well tolerated and demonstrated immunogenicity for both humoral and cell-mediated responses. In the study described herein, 25 rhesus macaques received prime and boost intramuscular (IM) immunizations of AdPfCA alone or with an ascending dose of 7DW8-5. Our results indicate that 7DW8-5 is safe and well-tolerated and provides a significant enhancement (up to 9-fold) in malaria-specific CD8+ T-cell responses after both priming and boosting phases, supporting further clinical development.

Co-administration of α-GalCer analog and TLR4 agonist induces robust CD8 + T-cell responses to PyCS protein and WT-1 antigen and activates memory-like effector NKT cells

“…7DW8-5 was recently tested by our group in a non-human primate (rhesus monkey) model. In fact, we have tested the adjuvant effect of 7DW8-5 for an adenovirus-based malaria vaccine in rhesus macaques and found that 7DW8-5 could enhance malaria-specific CD8+T-cell responses without showing notable reactogenicity [49]. …”

A Novel Glycolipid Antigen for NKT Cells That Preferentially Induces IFN-γ Production

“…For example, Ags that preferentially skew the immune response towards Th1 cytokine production could be useful as vaccine adjuvants and anti-cancer therapeutics (58, 59). Here we have characterized DB06-1, a GSL Ag that differs from the well-studied αGalCer by only a single atom.…”

Activation and Function of iNKT and MAIT Cells

“…Thus, activated iNKT cells reduced the parasitemia by increasing the production of IFNγ in liver (Gonzalez-Aseguinolaza et al, 2000). These findings have stimulated studies to determine if synthetic GSLs that activate iNKT cells could act as adjuvants as part of a malaria vaccine, with some promising preliminary results from a trial in primates (Padte et al, 2013). In the case of the P. berghei ANKA/rodent model of cerebral malaria, even in the absence of αGalCer, iNKT cells from different mouse strains influenced the outcome in terms of Th1/Th2 cytokine polarization, proinflammatory cytokine levels, pathogenesis, and fatality (Hansen, Siomos, Buckingham, Scalzo, & Schofield, 2003).…”