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Most bacterial vaccines work for a subset of bacterial strains or require the modification of the antigen or isolation of the pathogen before vaccine development. Here we report injectable biomaterial vaccines that trigger potent humoral and T-cell responses to bacterial antigens by recruiting, reprogramming and releasing dendritic cells. The vaccines are assembled from regulatorily approved products and consist of a scaffold with absorbed granulocyte-macrophage colony-stimulating factor and CpG-rich oligonucleotides incorporating superparamagnetic microbeads coated with the broad-spectrum opsonin Fc-mannose-binding lectin for the magnetic capture of pathogen-associated molecular patterns from inactivated bacterial-cell-wall lysates. The vaccines protect mice against skin infection with methicillin-resistant Staphylococcus aureus, mice and pigs against septic shock from a lethal Escherichia coli challenge and, when loaded with pathogen-associated molecular patterns isolated from infected animals, uninfected animals against a challenge with different E. coli serotypes. The strong immunogenicity and low incidence of adverse events, a modular manufacturing process, and the use of components compatible with current good manufacturing practice could make this vaccine technology suitable for responding to bacterial pandemics and biothreats.

The coronavirus disease 2019 (COVID‐19) pandemic demonstrates the importance of generating safe and efficacious vaccines that can be rapidly deployed against emerging pathogens. Subunit vaccines are considered among the safest, but proteins used in these typically lack strong immunogenicity, leading to poor immune responses. Here, a biomaterial COVID‐19 vaccine based on a mesoporous silica rods (MSRs) platform is described. MSRs loaded with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), the toll‐like receptor 4 (TLR‐4) agonist monophosphoryl lipid A (MPLA), and SARS‐CoV‐2 viral protein antigens slowly release their cargo and form subcutaneous scaffolds that locally recruit and activate antigen‐presenting cells (APCs) for the generation of adaptive immunity. MSR‐based vaccines generate robust and durable cellular and humoral responses against SARS‐CoV‐2 antigens, including the poorly immunogenic receptor binding domain (RBD) of the spike (S) protein. Persistent antibodies over the course of 8 months are found in all vaccine configurations tested and robust in vitro viral neutralization is observed both in a prime‐boost and a single‐dose regimen. These vaccines can be fully formulated ahead of time or stored lyophilized and reconstituted with an antigen mixture moments before injection, which can facilitate its rapid deployment against emerging SARS‐CoV‐2 variants or new pathogens. Together, the data show a promising COVID‐19 vaccine candidate and a generally adaptable vaccine platform against infectious pathogens., Mesoporous silica rods (MSRs) scaffolds are used as a platform to induce adaptive immunity against SARS‐CoV‐2 antigens. Sustained delivery of GM‐CSF, MPLA, and a variety of SARS‐CoV‐2 subunit immunogens from the MSR vaccine recruite immune cells into the scaffolds and consistently induce antigen‐specific long‐lasting antibodies, cytotoxic T lymphocyte responses (CTL), and viral neutralization in vitro.

Vaccines have shown significant promise in eliciting protective and therapeutic responses. However, most effective vaccines require several booster shots, and it is challenging to generate potent responses against small molecules and synthetic peptide antigens often used to increase target specificity and improve vaccine stability. As continuous antigen uptake and processing by APCs and persistent toll-like receptor (TLR) priming have been shown to amplify antigen specific humoral immunity, we explored whether a single injection of a mesoporous silica micro-rod (MSR) vaccine containing synthetic molecules and peptides can effectively generate potent and durable antigen-specific humoral immunity. A single injection of the MSR vaccine against a gonadotropin-releasing hormone (GnRH) decapeptide elicited highly potent anti-GnRH response that lasted for over 12 months. The MSR vaccine generated higher titers than bolus or alhydrogel alum vaccine formulations. Moreover, a MSR vaccine directed against a Her2/neu peptide within the Trastuzumab binding domain showed immunoreactivity to native Her2 protein on tumor cell surface and, when directed against nicotine, generated long-term anti-nicotine antibodies. Mechanistically, we found that the MSR vaccine induced persistent germinal center (GC) B-cell activity for more than 3 weeks after a single injection, generation of memory B cells, and that at least 7 days of immunostimulation by the vaccine was required to generate an effective humoral response. Together, these data suggest that the MSR vaccine represents a promising technology for synthetic antigen vaccines to bypass the need for multiple immunizations and enhance long-term production of antibodies against endogenous antigens in the context of reproductive biology, cancer, and chronic addiction.

Broad spectrum vaccines could provide a solution to the emergence of antibiotic resistant microbes, pandemics and engineered biothreat agents. Here, we describe a modular vaccine (composite infection vaccine technology (ciVAX)) which can be rapidly assembled and in which 4 of the 5 components are already approved for human use. ciVAX consists of an injectable biomaterial scaffold with factors to recruit and activate dendritic cells (DC) in vivo and microbeads conjugated with the broad-spectrum opsonin Fc-Mannose-binding Lectin (FcMBL) that is pre-bound to polysaccharide-rich cell wall antigens, such as the pathogen-associated molecular patterns (PAMPs) fractions, captured from whole inactivated bacteria. Vaccination of mice and rabbits with ciVAX generates potent humoral and T cell responses to PAMPs isolated from native antibiotic-resistant E. coli and S. aureus, and ciVAX protects mice and pigs against lethal E coli challenge in sepsis and septic shock models. In addition to the efficacy of ciVAX against homologous challenge, PAMPS isolated from an infected animal protects other animals against infection by heterologous challenge using different E. coli serotypes – demonstrating the potential for use of ciVAX in controlling pandemics. The advantage of the ciVAX technology is the strong immunogenicity with limited reactogenicity, the use of inactivated pathogens, and the modular manufacture using cGMP approved products which can be stockpiled ready for the next pandemic.One Sentence SummaryBiomaterial vaccine induces strong immunogenicity, weak reactogenicity, and protects from E. coli sepsis in rodents and pigs, and MRSA skin abscess.

Short peptides are the minimal modality of antigen recognized by cellular immunity and are therefore considered a safe and highly specific source of antigen for vaccination. Nevertheless, successful peptide immunotherapy is limited by the short half-life of peptide antigens in vivo as well as their weak immunogenicity. We recently reported a vaccine strategy based on dendritic cell-recruiting Mesoporous Silica Rod (MSR) scaffolds to enhance T-cell responses against subunit antigen. In this study, we investigated the effect of covalently conjugating peptide antigens to MSRs to increase their retention in the scaffolds. Using both stable thioether and reducible disulfide linkages, peptide conjugation greatly increased peptide loading compared to passive adsorption. In vitro, Bone Marrow derived Dendritic Cells (BMDCs) could present Ovalbumin (OVA)-derived peptides conjugated to MSRs and induce antigen-specific T-cell proliferation. Stable conjugation decreased presentation in vitro while reducible conjugation maintained levels of presentation as high as soluble peptide. Compared to soluble peptide, in vitro, expansion of OT-II T-cells was not affected by adsorption or stable conjugation to MSRs but was enhanced with reversible conjugation to MSRs. Both conjugation schemes increased peptide residence time in MSR scaffolds in vivo compared to standard bolus injections or a simple adsorption method. When MSR scaffolds loaded with GM-CSF and CpG-ODN were injected subcutaneously, recruited dendritic cells could present antigen in situ with the stable conjugation increasing presentation capacity. Overall, this simple conjugation approach could serve as a versatile platform to efficiently incorporate peptide antigens in MSR vaccines and potentiate cellular responses.

Vaccines have shown significant promise in eliciting protective and therapeutic responses. However, most effective vaccines require several booster shots, and it is challenging to generate potent responses against small molecules and synthetic peptide antigens often used to increase target specificity and improve vaccine stability. As continuous antigen uptake and processing by APCs and persistent toll-like receptor (TLR) priming have been shown to amplify antigen specific humoral immunity, we explored whether a single injection of a mesoporous silica micro-rod (MSR) vaccine containing synthetic molecules and peptides can effectively generate potent and durable antigen-specific humoral immunity. A single injection of the MSR vaccine against a gonadotropin-releasing hormone (GnRH) decapeptide elicited highly potent anti-GnRH response that lasted for over 12 months. The MSR vaccine generated higher titers than bolus or alhydrogel alum vaccine formulations. Moreover, a MSR vaccine directed against a Her2/neu peptide within the Trastuzumab binding domain showed immunoreactivity to native Her2 protein on tumor cell surface and, when directed against nicotine, generated long-term anti-nicotine antibodies. Mechanistically, we found that the MSR vaccine induced persistent germinal center (GC) B-cell activity for more than 3 weeks after a single injection, generation of memory B cells, and that at least 7 days of immunostimulation by the vaccine was required to generate an effective humoral response. Together, these data suggest that the MSR vaccine represents a promising technology for synthetic antigen vaccines to bypass the need for multiple immunizations and enhance long-term production of antibodies against endogenous antigens in the context of reproductive biology, cancer, and chronic addiction.

Biomaterials have shown substantial potential to integrate synergistically with current cancer vaccine strategies and enhance their effectiveness. We recently developed an injectable biomaterial vaccine via spontaneous assembly of mesoporous silica (MPS) microparticles into a 3D scaffold in vivo. When formulated with GM-CSF and the TLR-9 agonist CpG, the MPS vaccine modulates host dendritic cell (DC) activation and trafficking. Here we demonstrate that a single injection of the MPS vaccine induced persistent germinal center B cell activity for over 30 days. Consequently, when immunized with a small linear Her2/neu peptide within the Trastuzumab binding domain, the MPS vaccine elicited over 2 orders of magnitude higher IgG1 and IgG2a antibody titer compared to a traditional bolus vaccine, and the antibody exhibited immunoreactivity on the native Her2 structure on breast cancer cells. To further enhance CTL responses against tumor antigens, we co-presented the antigen with polyethylenimine (PEI) in the MPS vaccine. PEI increased antigen cross-presentation in murine DCs, and TNF-a and IL-6 production in both murine and human DCs in vitro. Compared to the MPS vaccine, the MPS-PEI vaccine enhanced activated and antigen+ DCs in the vaccine and the vaccine draining lymph node by ~2 fold. Systemically, using both OVA and a HPV-E7 peptide as antigens, the MPS-PEI vaccine induced ~2.5 fold higher IFN-y producing antigen specific circulating CD8+ T-cells compared to the MPS vaccine. Impressively, using a HPV-E7 expressing tumor model, we demonstrated that a single injection of the MPS-PEI vaccine completely eradicated large established tumors in over 80% of mice. Finally, when immunized with a pool of recently sequenced B16 melanoma neoantigen peptides, the MPS-PEI vaccine induced potent therapeutic tumor growth control and synergy with anti-CTLA4 checkpoint blockade therapy. These findings suggest that the MPS vaccine may serve as a facile multifunctional and multi-epitope platform to modulate host immune cell function and augment personalized antitumor immunity. Citation Format: Aileen W. Li, Maxence O. Dellacherie, Miguel Sobral, Omr O. Ali, Jaeyun Kim, David J. Mooney. DC-recruiting biomaterial vaccine to enhance antitumor immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B119.