A gold glyco-nanoparticle carrying a listeriolysin O peptide and formulated with Advax™ delta inulin adjuvant induces robust T-cell protection against listeria infection

Abstract

In the search for an effective vaccine against the human pathogen, Listeria monocytogenes (Listeria), gold glyconanoparticles (GNP) loaded with a listeriolysin O peptide LLO91-99 (GNP-LLO) were used to immunise mice, initially using a dendritic cell (DC) vaccine approach, but subsequently using a standard parenteral immunisation approach. To enhance vaccine immunogenicity a novel polysaccharide adjuvant based on delta inulin (Advax™) was also co-formulated with the GNP vaccine. Confirming previous results, DC loaded in vitro with GNP-LLO provided better protection against listeriosis than DC loaded in vitro using free LLO peptide. The immunogenicity of GNP-LLO loaded DC vaccines was further increased by addition of Advax™ adjuvant. However, as DC vaccines are expensive and impracticable for prophylactic use, we next asked whether the same GNP-LLO antigen could be used to directly target DC in vivo. Immunisation of mice with GNP-LLO plus Advax™ adjuvant induced LLO-specific T-cell immunity and protection against Listeria challenge. Protection correlated with an increased frequency of splenic CD4(+) and CD8(+) T cells, NK cells and CD8α(+) DC, and Th1 cytokine production (IL-12, IFN-γ, TNF-α, and MCP-1), post-challenge. Enhanced T-cell epitope recruitment post-challenge was seen in the groups that received Advax™ adjuvant. Immunisation with GNP-LLO91-99 plus Advax™ adjuvant provided equally robust Listeria protection as the best DC vaccine strategy but without the complexity and cost, making this a highly promising strategy for development of a prophylactic vaccine against listeriosis.

Pregnancy Vaccination with Gold Glyco-Nanoparticles Carrying Listeria monocytogenes Peptides Protects against Listeriosis and Brain- and Cutaneous-Associated Morbidities

“…Vaccination of systemic listeriosis reduced IL-6 levels (Th2 pattern) and presented a significant increase in IL-12 levels (Th1 pattern) [11]. Here, we confirmed that neonatal listeriosis also caused MG to produce high levels of TNF-a (panel c, Figure 2) and IL-6 (Table 3), as reported in most neonatal human meningitis [1,29].…”

“…We have successfully developed dendritic cell vaccines loaded with LM peptides and deciphered that two peptides from this pathogen’s virulence factors, listeriolysin O (LLO) and glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), LLO 91–99 and GAPDH 1–22 , conferred significant listeriosis protection in two mice models sensitive and resistant to listeriosis [8,9,10]. We have also prepared a gold glyconanoparticle (GNP) coupled to the LLO 91–99 peptide formulated with an adjuvant and achieved good vaccine effectiveness in adult mice [11]. Indeed, the application of nanotechnology in immunology is creating big expectations in the field of vaccination [12] and many examples of nanoparticles (NP) have appeared in the literature [13,14].…”

“…In fact, nanoparticles are promising vector systems to explore vaccination during pregnancy against infectious agents [22]. The interesting results obtained with GNP-LLO 91–99 [11] prompted us to prepare other glyconanoparticles, GNP-GAPDH 1–22 , and examine the ability of these two vaccine vectors, GNP-LLO 91–99 and GNP-GAPDH 1–22 , to protect fetuses from listeriosis. For this purpose, we vaccinated pregnant mothers with the above-mentioned glyconanoparticles formulated with adjuvants and followed LM infection during pregnancy and the neonatal period as well as the morbidities associated with neonatal listeriosis.…”

Biomarker Tools to Design Clinical Vaccines Determined from a Study of Annual Listeriosis Incidence in Northern Spain

“…In this regard, DC or synthetic vaccines containing GADPH 1–22 epitopes and targeted to DC seemed to confer protection against experimental listeriosis, promoting Th1-Th17 and CD4 + -CD8 + T cell immune responses (20, 21, 30, 34). Here, we report that GAPDH 1–22 epitopes can activate MoDC of listeriosis patients with cancer receiving chemotherapy to release high levels TNF-α while low production of IL-6 and IL-10, a clear Th1 cytokine pattern.…”

Novel nanoparticle vaccines for Listeriosis

“…16 They were therefore used to generate a Listeria based GNP nanovaccine by covalent linking of glucose and a peptide representing the Listeria T-cell epitope (LLO [91][92][93][94][95][96][97][98][99] ) to the GNP metallic core thereby creating GNP-LLO 91-99 nanoparticles. 17 The aim was to improve upon the effectiveness previously seen with a DC vaccine loaded with LLO 91-99 peptide that induced CD8 T-cell responses and IFN-g levels 6,9,18 but only modest Listeria protection. The GNP-LLO 91-99 nanovaccine was shown to be free of cytoxicity, effectively delivered the Listeria epitope to DC in vitro and in vivo and induced effective CD8 C T-cell immunity.…”