Abstract
Vaccination is the most effective prophylactic tool against infectious diseases. Despite continued efforts to control malaria, the disease still generally represents a significant unmet medical need. Microcrystalline tyrosine (MCT) is a well described depot used in licensed allergy immunotherapy products and in clinical development. However, its proof of concept in prophylactic vaccines has only recently been explored. MCT has never been used in combination with virus-like particles (VLPs), which are considered to be one of the most potent inducers of cellular and humoral immune responses in mice and humans. In the current study we assessed the potential of MCT to serve as an adjuvant in the development of a vaccine against malaria either alone or combined with VLP using Plasmodium vivax thrombospondin-related adhesive protein (TRAP) as a target antigen. We chemically coupled PvTRAP to VLPs derived from the cucumber mosaic virus fused to a universal T-cell epitope of the tetanus toxin (CMVtt), formulated with MCT and compared the induced immune responses to PvTRAP formulated in PBS or Alum. The protective capacity of the various formulations was assessed using Plasmodium berghei expressing PvTRAP. All vaccine formulations using adjuvants and/or VLP increased humoral immunogenicity for PvTRAP compared to the antigen alone. The most proficient responder was the group of mice immunized with the vaccine formulated with PvTRAP-VLP + MCT. The VLP-based vaccine formulated in MCT also induced the strongest T cell response and conferred best protection against challenge with recombinant Plasmodium berghei. Thus, the combination of VLP with MCT may take advantage of the properties of each component and appears to be an alternative biodegradable depot adjuvant for development of novel prophylactic vaccines.
Highlights
Malaria is a massive global health problem [1,2,3]
When comparing mice vaccinated with only protein with protein plus alum adjuvants, there was no statistical difference in survival, but if those groups are compared with Microcrystalline tyrosine (MCT) and or virus-like particles (VLPs), there is a significant difference in survival
Our results clearly show that Plasmodium vivax thrombospondin-related adhesive protein (PvTRAP) conjugated increased survival compared to the group vaccinated with phosphate-buffered saline (PBS)
Summary
Malaria is a massive global health problem [1,2,3]. The World Health Organization (WHO), estimated in December 2015 the occurrence of 214 million cases and 438,000 deaths caused by malaria worldwide [4]. TRAP has been reported to be a target for T cell-based vaccines, but some studies have shown the importance of antibodies against TRAP as protective effector molecules against malaria [9,10,11]. Alum has no biological function, is non-biodegradable and has been associated with Th2 responses which promote secretion of proinflammatory cytokines such as interleukin (IL)-1 and cell apoptosis [14,20,21] These disadvantages encourage the use of natural and biodegradable alternative platforms that can support the immunological effect of a specific therapy. Virus-like particles (VLPs) have a high capacity to induce strong humoral and cellular immune responses [24,25,26] and may have the potential to increase vaccine efficacy against malaria in particular if combined with MCT to create a synergistic adjuvant system. We assessed the ability of MCT to enhance the immunogenicity of Plasmodium vivax thrombospondin-related adhesive protein (PvTRAP) in free form or conjugated to VLPs and to protect against infection with Plasmodium bergei expressing P. vivax TRAP [27]
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