Immune stimulating
agents like Toll-like receptor 7 (TLR7)
agonists
induce potent antitumor immunity but are limited in their therapeutic
window due to off-target immune activation. Here, we developed a polymeric
delivery platform that binds excess unpaired cysteines on tumor cell
surfaces and debris to adjuvant tumor neoantigens as an in
situ vaccine. The metabolic and enzymatic dysregulation in
the tumor microenvironment produces these exofacial free thiols, which
can undergo efficient disulfide exchange with thiol-reactive pyridyl
disulfide moieties upon intratumoral injection. These functional monomers
are incorporated into a copolymer with pendant mannose groups and
TLR7 agonists to target both antigen and adjuvant to antigen presenting
cells. When tethered in the tumor, the polymeric glyco-adjuvant induces
a robust antitumor response and prolongs survival of tumor-bearing
mice, including in checkpoint-resistant B16F10 melanoma. The construct
additionally reduces systemic toxicity associated with clinically
relevant small molecule TLR7 agonists.
Salmonella typhimurium hybrids expressing the S. typhosa antigens 9, d, and Vi were constructed by genetic crosses with an S. typhosa Hfr donor. The hybrids retained the same degree of mouse virulence as their S. typhimurium parent strain, the minimum lethal dose being less than 50 organisms when tested either in C57 black mice or Swiss white mice. Vaccination of the Swiss white mice with S. typhosa Ty2 vaccines prepared by acetone treatment, alcohol treatment, or heat-killing conferred significant protection against challenge by the hybrid strains but not against their S. typhimurium parent. Both the acetone-treated and alcohol-treated typhoid vaccines were markedly more protective than the heat-killed, phenol-preserved vaccine.
The SARS-CoV-2 virus has caused an unprecedented global crisis, and curtailing its spread requires an effective vaccine which elicits a diverse and robust immune response. We have previously shown that vaccines made of a polymeric glyco-adjuvant conjugated to an antigen were effective in triggering such a response in other disease models and hypothesized that the technology could be adapted to create an effective vaccine against SARS-CoV-2. The core of the vaccine platform is the copolymer p(Man-TLR7), composed of monomers with pendant mannose or a toll-like receptor 7 (TLR7) agonist. Thus, p(Man-TLR7) is designed to target relevant antigen-presenting cells (APCs) via mannose-binding receptors and then activate TLR7 upon endocytosis. The p(Man-TLR7) construct is amenable to conjugation to protein antigens such as the Spike protein of SARS-CoV-2, yielding Spike-p(Man-TLR7). Here, we demonstrate Spike-p(Man-TLR7) vaccination elicits robust antigen-specific cellular and humoral responses in mice. In adult and elderly wild-type mice, vaccination with Spike-p(Man-TLR7) generates high and long-lasting titers of anti-Spike IgGs, with neutralizing titers exceeding levels in convalescent human serum. Interestingly, adsorbing Spike-p(Man-TLR7) to the depot-forming adjuvant alum amplified the broadly neutralizing humoral responses to levels matching those in mice vaccinated with formulations based off of clinically-approved adjuvants. Additionally, we observed an increase in germinal center B cells, antigen-specific antibody secreting cells, activated T follicular helper cells, and polyfunctional Th1-cytokine producing CD4
+
and CD8
+
T cells. We conclude that Spike-p(Man-TLR7) is an attractive, next-generation subunit vaccine candidate, capable of inducing durable and robust antibody and T cell responses.
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