Adjuvant-carrying synthetic vaccine particles augment the immune response to encapsulated antigen and exhibit strong local immune activation without inducing systemic cytokine release

📖 Top 20% JournalMar 6, 2014Vaccine

Synthetic vaccine particles with boosters strengthen immune response near the injection site without causing widespread inflammation

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Abstract

Co-delivery of an antigen with TLR7/8 or TLR9 agonists in synthetic polymer nanoparticles results in a strong augmentation of immune responses with minimal systemic inflammation.

Antigen encapsulated in nanoparticles with TLR agonists shows significantly enhanced humoral and cellular immune responses compared to free TLR agonists.
Inflammatory cytokine levels, such as TNF-a and IL-6, are 50- to 200-fold higher with free TLR7/8 agonists than with nanoparticle-encapsulated versions.
Local immune stimulation is more pronounced and sustained when using SVP-encapsulated TLR agonists, leading to greater cellular infiltration in lymph nodes.
Synthetic vaccine particle technology allows for the effective use of CpG oligonucleotides, which are otherwise quickly degraded in the body.
The SVP platform may facilitate the clinical application of TLR agonists as adjuvants in vaccines requiring strong immune responses.

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Augmentation of immunogenicity can be achieved by particulate delivery of an antigen and by its co-administration with an adjuvant. However, many adjuvants initiate strong systemic inflammatory reactions in vivo, leading to potential adverse events and safety concerns. We have developed a synthetic vaccine particle (SVP) technology that enables co-encapsulation of antigen with potent adjuvants. We demonstrate that co-delivery of an antigen with a TLR7/8 or TLR9 agonist in synthetic polymer nanoparticles results in a strong augmentation of humoral and cellular immune responses with minimal systemic production of inflammatory cytokines. In contrast, antigen encapsulated into nanoparticles and admixed with free TLR7/8 agonist leads to lower immunogenicity and rapid induction of high levels of inflammatory cytokines in the serum (e.g., TNF-a and IL-6 levels are 50- to 200-fold higher upon injection of free resiquimod (R848) than of nanoparticle-encapsulated R848). Conversely, local immune stimulation as evidenced by cellular infiltration of draining lymph nodes and by intranodal cytokine production was more pronounced and persisted longer when SVP-encapsulated TLR agonists were used. The strong local immune activation achieved using a modular self-assembling nanoparticle platform markedly enhanced immunogenicity and was equally effective whether antigen and adjuvant were co-encapsulated in a single nanoparticle formulation or co-delivered in two separate nanoparticles. Moreover, particle encapsulation enabled the utilization of CpG oligonucleotides with the natural phosphodiester backbone, which are otherwise rapidly hydrolyzed by nucleases in vivo. The use of SVP may enable clinical use of potent TLR agonists as vaccine adjuvants for indications where cellular immunity or robust humoral responses are required.

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Abstract

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