Malaria vaccine research has been ongoing since the 1980s with limited success. However, recent improvements in our understanding of the immune responses required to combat each stage of infection will allow for intelligent design of both antigens and their associated delivery vaccine vehicles/vectors. Synthetic carriers (also known as vectors) are usually particulate and have multiple properties, which can be varied to control how an associated vaccine interacts with the host, and consequently how the immune response develops. This review comprehensively analyzes both historical and recent studies in which synthetic carriers are used to deliver malaria vaccines. Furthermore, the requirements for a synthetic carrier, such as size, charge, and surface chemistry are reviewed in order to understand the design of effective particle-based vaccines against malaria, as well as providing general insights. Synthetic carriers have the ability to alter and direct the immune response, and a better control of particle properties will facilitate improved vaccine design in the near future.

Vaccines against blood-stage malaria often aim to induce antibodies to neutralize parasite entry into red blood cells, interferon gamma (IFNγ) produced by T helper 1 (Th1) CD4+ T cells or interleukin 4 (IL-4) produced by T helper 2 (Th2) cells to provide B cell help. One vaccine delivery method for suitable putative malaria protein antigens is the use of nanoparticles as vaccine carriers. It has been previously shown that antigen conjugated to inorganic nanoparticles in the viral-particle size range (~40–60 nm) can induce protective antibodies and T cells against malaria antigens in a rodent malaria challenge model. Herein, it is shown that biodegradable pullulan-coated iron oxide nanoparticles (pIONPs) can be synthesized in this same size range. The pIONPs are non-toxic and do not induce conventional pro-inflammatory cytokines in vitro and in vivo. We show that murine blood-stage antigen MSP4/5 from Plasmodium yoelii could be chemically conjugated to pIONPs and the use of these conjugates as immunogens led to the induction of both specific antibodies and IFNγ CD4+ T cells reactive to MSP4/5 in mice, comparable to responses to MSP4/5 mixed with classical adjuvants (e.g., CpG or Alum) that preferentially induce Th1 or Th2 cells individually. These results suggest that biodegradable pIONPs warrant further exploration as carriers for developing blood-stage malaria vaccines.

Vaccines are a powerful and cost-effective tool to limit the spread of disease, however, there are still some complex diseases for which we don’t yet have a successful and long-lasting vaccine, for example malaria and cancers. One reason for this is the difficult choice of target antigen, though there is also a need for potent adjuvants/delivery systems capable of inducing both antibody and T cell responses. Current licensed adjuvants, for example Alum, mainly elicit strong antibody responses, therefore, novel vaccine delivery systems need to be developed. One such system is by utilising nanoparticles to increase the vaccine induced immune response. Inorganic carboxylated polystyrene nanoparticles in the viral size range (40–50nm) are non-inflammatory, stable in solution, and target dendritic cells. Importantly, these nanoparticles elicit potent antibody, CD4+ T cell and CD8+ T cell responses to a range of antigens in murine studies, including to malaria and cancer peptides. Using fluorescent nanoparticles allows us to assess the interaction of these nanoparticles with specific cell subsets, such as antigen presenting cells, by flow cytometry. Furthermore, we can analyse the biodistribution of the nanoparticles using small animal imaging via the IVIS. Ideally, for maximum translation capacity into human vaccines these nanoformulations would be biodegradable. In addition to our model polystyrene nanovaccines we have been investigating biodegradable nanoparticles made from other materials, i.e. iron oxide. Comparable to polystyrene nanoparticles, biodegradable nanovaccines are also endocytosed by dendritic cells and are capable of inducing antibodies and cytokine secretion from both CD4+ T cells and CD8+ T cells.

For vaccines targeting diseases such as malaria and cancer, CD8 T cell responses are vital. Traditional adjuvants, like alum, are incapable of inducing these responses and thus new delivery strategies are required. Previously, we have shown that biocompatible polystyrene nanoparticles (PSNPs) (carboxylate, 40–50 nm) can induce potent cytotoxic T cell and antibody responses when conjugated to antigen and can protect mice against experimental tumours or clear large established tumours after a single immunization. As a biodegradable alternative; we synthesised ~50 nm iron oxide nanoparticles (IONPs) stabilized with the polysaccharide pullulan. The IONPs share similar characteristics (size, charge and shape) with the PSNPs, are stable, non-toxic, rapidly taken up by dendritic cells in vitro and are considered inert as they do not upregulate costimulatory markers. The adjuvant/carrier capabilities of IONPs when conjugated to model antigen ovalbumin (OVA) were assessed in vivo. IONPs can induce strong antibody responses but failed to boost the T cell response (Th1 and Th2) after two immunisations, despite their similarity to PSNPs. This implies that the composition of a NP can affect its interactions with the immune system and as such its behaviour as a carrier. To produce an IONP delivery system in which CD8 T cells could also be induced in addition to strong antibody responses, IONPs were co-delivered with the TLR9 agonist CpG. This led to > 2-fold increases in CD8 T cell and antibody responses above either IONPs or CpG alone. Therefore, these biodegradable particles have the capacity to synergize with an inflammatory adjuvant and provide a new strategy for vaccine delivery focused on the induction of CD8 T cell responses.

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