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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.

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.

Complex diseases (such as malaria) exhibit high degrees of antigenic polymorphism and complex life cycles. These have hindered the development of vaccine formulations capable of promoting strong, long-lasting protection against such diseases, with the incorporation of antigens against multiple life cycle stages a current research focus. With traditional adjuvants such as alum, even the most promising antigenic vaccine targets may be unable to effectively protect populations from infection as the immune responses they promote are of insufficient strength or nature. As such, improved vaccine delivery and adjuvant systems need to be developed. This work outlines the development of pullulan-coated iron oxide nanoparticles (IOs) and their use as vaccine carriers/adjuvants. It explores particle synthesis, characterisation of toxicity, stability and biodegradability, as well asthe assessment of IO adjuvanticity alone or when mixed with an immunomodulatory synthetic oligodeoxynucleotide (CpG ODN) which specifically agonises toll-like receptor 9 (TLR9), expressed on innate immune cells.An array of different nanoparticles has been reported as potential carriers, with their stimulatory capacities highly dependent on their properties, notably size, shape, charge and composition. The majority of these constructs are either non-biodegradable or significantly larger than the viral size range (40-60 nm) which allows drainage to the local lymph nodes and enables direct interaction with antigen presenting cells (APCs) in this organ. The two IOs developed in this work meet both the size and degradability requirements, but differ in iron oxide structure. This leads to particles with contrasting degradation and stability profiles, with differing capacities to act as antigen delivery vehicles. IO2s with an oxyhydroxide core consistently promote strong humoral immune responses against conjugated model antigen, ovalbumin (OVA), highly comparable to CpG. However, they do not induce T cell responses. Given this profile, their suitability as carriers for a blood stage malaria antigen, merozoite surface protein 4/5 (MSP4/5) is assessed. Antibodies and Th1 memory cells, the key mediators against blood stage infection, were produced, demonstrating the promise of IO2s in this area. To widen the applicability of these particles, their suitability in combination with CpG is also investigated. Remarkably, the co-delivery strategy produces very strong CD8+ T cell responses, regardless of whether OVA is conjugated or simply mixed in. To better understand this synergism, the effects of the adjuvants on the early innate immune response are investigated. While IO2s do not alter systemic cytokine levels (48 hours after injection), there are changes in the activation state of infiltrating macrophages. This implies that the modulation of the innate immune state by CpG is providing a suitable microenvironment for IO2s to stimulate adaptive CD8+ T cell responses. To further investigate this phenomenon, the mechanisms underlying IO2 uptake by cells are examined. Uptake is initiated by the binding of IO2s to the scavenger receptor SR-A1 (MSR1), widely expressed on APCs. In the draining lymph node, this leads to uptake by macrophages, the population expanded by CpG, indicating a potential role for these cells in stimulating adaptive response development. In summary, the IOs developed in this work demonstrate potential as carriers for different subunit vaccines, including those against malaria, both alone and in concert with CpG.