Biology subjects

Doherty, E. J.

Publications and source records attributed to Doherty, E. J..

3 recordsLinked to original sources

bioRxiv2020

A rapidly adaptable biomaterial vaccine for SARS-CoV-2

ABSTRACTThe global COVID-19 pandemic motivates accelerated research to develop safe and efficacious vaccines. To address this need, we leveraged a biomaterial vaccine technology that consists of mesoporous silica rods (MSRs) that provide a sustained release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and adjuvants to concentrate and mature antigen-presenting cells at the vaccine site. Here we explored the humoral responses resulting from the use of monophosphoryl lipid A (MPLA) as the adjuvant and SARS-CoV-2 spike proteins S1, S2, the nucleocapsid (N) protein, and receptor binding domain (RBD) as the target antigens. The dose of antigen and impact of pre-manufacturing of vaccines as versus loading antigen just-in-time was explored in these studies. Single shot MSR vaccines induced rapid and robust antibody titers to the presented antigens, even without the use of a boost, and sera from vaccinated animals demonstrated neutralizing activity against a SARS-CoV-2 pseudovirus. Overall, these results suggest the MSR vaccine system may provide potent protective immunity when utilized to present SARS-CoV-2 antigens.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2020

Single-shot Mesoporous Silica Rods Scaffold for Induction of Humoral Responses Against Small Antigens

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.

bioengineering↗

bioRxiv2020

Modular biomaterials vaccine technology protects against multiple pathogens and septic shock

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.

immunology↗