Biology subjects

Brandt, D. S.

Publications and source records attributed to Brandt, D. S..

3 recordsLinked to original sources

bioRxiv2025

The ID93 + GLA-3M-052-LS vaccine candidate elicits mucosal and systemic immunogenicity and protective efficacy against Mycobacterium tuberculosis challenge in BCG-primed Collaborative Cross inbred mice

New vaccine approaches are needed against tuberculosis (TB). We sought to optimize mucosal immunogenicity and protective efficacy by modulating the adjuvant component and route of immunization of a next-generation TB vaccine using the recombinant TB vaccine antigen (Ag) ID93. ID93-specific mucosal and systemic immunogenicity and protective efficacy were assessed in the Collaborative Cross 004 mouse strain, a mouse strain susceptible to Mycobacterium tuberculosis (Mtb) infection, as a suitable model of Mtb susceptible populations. Immunogenicity data from various vaccine candidates were used to select lead vaccine candidates with the most preferred immunostimulatory profiles using a pre-determined desirability index. A liposomal adjuvant system containing synthetic TLR4 and TLR7/8 ligands (GLA-3M-052-LS), administered by a heterologous intramuscular-intranasal regimen, induced an optimal comprehensive immune response profile including high levels of mucosal antibody and Th1 CD4+ T cells in the lungs. In BCG-primed mice, immunization with intramuscular followed by intranasal ID93 + GLA-3M-052-LS boosts significantly reduced Mtb burden in the lungs after challenge vs. BCG vaccinated mice alone. Thus, ID93 + GLA-3M-052-LS represents a promising next-generation TB vaccine candidate suitable for testing in additional preclinical models.

immunology↗

bioRxiv2025

A Spray Dried Replicon Vaccine Platform for Pandemic Response

The recent COVID-19 pandemic, as well as the threat of a global pandemic caused by H5N1 avian influenza virus, has highlighted the need for the development of thermostable vaccines that can be manufactured and distributed rapidly to combat the next global pandemic. To address this need, we previously developed a replicon vaccine platform that utilizes a nanostructured lipid carrier (NLC) to protect and efficiently deliver antigen-expressing replicon molecules in vivo. The replicon-NLC vaccine platform uses readily sourced components and can be rapidly manufactured at scale with the potential for stockpiling, thus enhancing pandemic preparedness. Spray drying is a promising method of vaccine desiccation with reduced costs and increased scale-up capabilities compared to lyophilization. As proof of concept, we demonstrate for the first time the successful spray drying of a replicon-NLC vaccine complex designed to protect against H5N1 avian influenza A virus to enhance its long-term thermostability while maintaining vaccine immunogenicity in an in vivo mouse model. Several glass-forming disaccharide excipients were screened for formulation and process compatibility under low-temperature spray drying conditions, and it was determined that a suitable shell-forming excipient, L-leucine, was necessary to prevent excessive accumulation of replicon-NLC vaccine complexes on the dry powder surface and a subsequent loss in process yield. The spray dried replicon-NLC vaccine powders were chemically stable for 1 month of storage at 40{degrees}C. Immunogenicity of the spray dried drug product was also well maintained for at least 3 months of storage at 4{degrees}C when administered intramuscularly into C57BL/6 mice as a reconstituted liquid. Finally, we demonstrate the ability to precisely control the aerodynamic particle size of the spray dried vaccine product to generate dry powders that are theoretically suitable for nasal or pulmonary delivery without reconstitution. This work establishes the feasibility of spray drying a thermostable replicon-NLC vaccine for rapid pandemic response.

immunology↗

bioRxiv2025

Development of an Intranasally- and Intramuscularly-Administrable Replicon Vaccine Efficacious Against H5N1 Influenza Virus

The risk of a respiratory viral pandemic is significant, including from the now widespread panzootic H5N1 influenza virus, highlighting the need for effective, stable, and inexpensive vaccine technologies that elicit strongly protective immunity. Intranasal vaccines can stimulate local immune responses at the site of natural respiratory viral infection, a key characteristic that can not only reduce morbidity and mortality caused by respiratory viruses but also potentially reduce viral transmissibility to limit outbreaks. Nucleic acid vaccines are now a valuable tool in pandemic responses, with high potency and rapid adaptability to target circulating or emerging viral strains; however, data are limited on which vaccine attributes are needed for efficient transmucosal delivery and immune stimulation following intranasal delivery. To demonstrate proof of concept, here we have developed a replicon vaccine expressing an H5 influenza antigen that uses a nanostructured lipid carrier (NLC) delivery system. A relationship was established between the molar ratio of positive charges on the NLC to the negative charges on the nucleic acid (N:P ratio) and the immunogenicity of the vaccine formulations, with higher N:P ratios resulting in an increase in vaccine immunogenicity. We demonstrated the ability of this replicon vaccine to be administered via intramuscular and intranasal routes with a singular vaccine formulation. The vaccine induced systemic immunity when dosed intramuscularly or intranasally in an immunocompetent mouse model, whereas intranasal dosing uniquely stimulated a strong mucosal immune response. Moreover, a mixed intramuscular/intranasal dosing strategy using this unified formulation stimulated a balanced systemic and mucosal immune response. Finally, we demonstrated the protective efficacy of this intranasally and intramuscularly/intranasally delivered H5 replicon-NLC vaccine against morbidity and mortality in a lethal H5N1 influenza challenge ferret model. This work establishes the replicon-NLC vaccine platform as a potential novel intranasal technology for rapid pandemic response.

immunology↗