Antigen-Dependent Adjuvanticity of Poly(lactic-co-glycolic acid)-polyethylene Glycol 25% Nanoparticles for Enhanced Vaccine Efficacy

<b>Background</b>: A key component in modern vaccine development is the adjuvant, which enhances and/or modulates the antigen-specific immune response. In recent years, nanoparticle (NP)-based adjuvants have attracted much research attention owing to their ability to enhance vaccine potency. Nonetheless, how the selection of different antigens influences the overall vaccine efficacy when combined with the same nanoparticle adjuvant is less discussed, which is important for practical applications. <b>Methods</b>: Non-toxic mutants of exotoxin Hla (rHlaH35L) and cell-wall-anchored protein SpA(rSpam) were covalently conjugated to Poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) 25% NPs (25% NPs) as antigens to prepare nanovaccines. Antibody titers, cytokine secretion levels, and the antibody bacteriolytic capacity were tested to investigate immune activation. To evaluate the protective efficacy of the nanovaccine, immunized mice were challenged with <i>S. aureus</i> ATCC 25923 at three different lethal doses: 1 × LD₁₀₀, 2 × LD₁₀₀, and 4 × LD₁₀₀. <b>Results</b>: We showed that 25% NP-rHlaH35L nanovaccines were associated with more efficient humoral, cellular, and innate immune responses and protection potency compared with 25% NP-rSpam. Moreover, the overall vaccine potency of 25% NP-rHlaH35L was even better than the combination vaccination of both 25% NP-rHlaH35L and 25% NP-rSpam. In comparison to the clinically used aluminum (alum) adjuvant, the 25% NP adjuvants were found to stimulate humoral and cellular immune responses efficiently, irrespective of the antigen type. For antigens, either exotoxins or cell-wall-anchored proteins, the 25% NP-based vaccines show excellent protection for mice from <i>S. aureus</i> infection with survival rates of 100% after lethal challenge, which is significantly superior to the clinically used alum adjuvant. Moreover, due to the superior immune response elicited by 25% NP-rHlaH35L, the animals inoculated with this formulation survived even after two times the lethal dose of <i>S. aureus</i> administration. <b>Conclusions</b>: We demonstrated that the type of antigen plays a key role in determining the overall vaccine efficacy in the immune system when different kinds of antigens are conjugated with a specific nanoparticle adjuvant, paving a new way for vaccine design based on 25% NP adjuvants with enhanced potency and reduced side effects.