A Trojan horse: Chemical boosting of Plasmodium falciparum whole sporozoite vaccine immunogenicity

Abstract

In non-endemic healthy adults, late-arresting whole sporozoite vaccines have demonstrated a high protective efficacy. To further increase the vaccine potency, we explored options to boost immunogenicity by chemically augmenting SPZ with adjuvants. Key features herein lie in the introduction of chemicals that boost the unique immunogenicity of the SPZ without harming their viability and infectivity. We synthesized two positively charged dye-adjuvant complexes (Cy5-CL307 and Cy5-MDP) that accumulate in SPZs through their mitochondrial potential. Following labelling, the stability of the label was tested. We were able to adjuvant on average 90 % of SPZ with either adjuvant, yielding SPZ^CL307 or SPZ^MDP. Both types of adjuvanted SPZ remained viable (84 % vs 71 %, respectively), motile (78.7 % vs 83.6 %, respectively) and as infective as non-adjuvanted control SPZ. Critically, the loading of adjuvants increased the immunogenicity of the SPZ, as evidenced by the enhanced expression of CD80, CD25, IL-6, IL-8, TNF, IL-1β and IL-10 in monocyte-derived macrophages when stimulated with SPZ^CL307, but not SPZ^MDP (p = 0.018, p = 0.043, p = 0.018, p = 0.018, p = 0.028, p = 0.028 and p = 0.018, respectively). These increases in activation by SPZ^CL307 also translated to 18 % increased CD137 expression (p = 0.01) in circumsporozoite-specific memory CD8⁺ T cells and a trend of 1.6-fold increased expression of perforin (p = 0.064). Our findings indicate that SPZ can be adjuvanted without affecting their viability and infectivity. For SPZ^CL307, but not SPZ^MDP, we found evidence of increased immune activation in in vitro setups and enhanced capacity to boost memory T cell responses. Further optimization of the adjuvanting strategy could help optimize vaccine dosing regimens in the future.

Keywords: Adjuvant-antigen complex; Genetically attenuated parasite; Malaria; Plasmodium falciparum; Whole-sporozoite vaccine.