Publications by authors named "Benjamin Cossette"

8 Publications

  • Page 1 of 1

Titrating Polyarginine into Nanofibers Enhances Cyclic-Dinucleotide Adjuvanticity and after Sublingual Immunization.

ACS Biomater Sci Eng 2021 Mar 27. Epub 2021 Mar 27.

Biomedical Engineering Department, Duke University, Durham, North Carolina 27708, United States.

Effective sublingual peptide immunization requires overcoming challenges of both delivery and immunogenicity. Mucosal adjuvants, such as cyclic-dinucleotides (CDN), can promote sublingual immune responses but must be codelivered with the antigen to the epithelium for maximum effect. We designed peptide-polymer nanofibers (PEG-Q11) displaying nona-arginine (R9) at a high density to promote complexation with CDNs bidentate hydrogen-bonding with arginine side chains. We coassembled PEG-Q11 and PEG-Q11R9 peptides to titrate the concentration of R9 within nanofibers. , PEG-Q11R9 fibers and cyclic-di-GMP or cyclic-di-AMP adjuvants had a synergistic effect on enhancing dendritic cell activation that was STING-dependent and increased monotonically with increasing R9 concentration. The polyvalent display of R9 on assembled nanofibers was significantly more effective at promoting CDN-mediated DC activation than mixing nanofibers with an equimolar concentration of unassembled R9 peptide. The sublingual administration of nanofibers revealed a bell-shaped trend between increasing R9 concentration and enhancements to antigen trafficking and the activation of DCs in the draining lymph nodes. Intermediate levels of R9 within sublingually administered PEG-Q11 fibers were optimal for immunization, suggesting a balance between polyarginine's ability to sequester CDNs along the nanofiber and its potentially detrimental mucoadhesive interactions. These findings present a potentially generalizable biomaterial strategy for enhancing the potency of CDN adjuvants and reveal important design considerations for the nascent field of sublingual biomaterial immunization.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01429DOI Listing
March 2021

Tabletized Supramolecular Assemblies for Sublingual Peptide Immunization.

Adv Healthc Mater 2021 03 26;10(6):e2001614. Epub 2021 Feb 26.

Biomedical Engineering Department, Duke University, Durham, NC, 27708, USA.

Widespread vaccination is essential to global health. Significant barriers exist to improving vaccine coverage in lower- and middle-income countries, including the costly requirements for cold-chain distribution and trained medical personnel to administer the vaccines. A heat-stable and highly porous tablet vaccine that can be administered sublingually via simple dissolution under the tongue is described. SIMPL tablet vaccines (Supramolecular IMmunization with Peptides subLingually) are produced by freeze-drying a mixture of self-assembling peptide-polymer nanofibers, sugars, and adjuvant. Sublingual immunization with SIMPL tablets raises antibody responses against both a model epitope from ovalbumin and a clinically relevant epitope from Mycobacterium tuberculosis. Further, sublingual antibody responses are not diminished after heating the tablets for 1 week at 45 °C, in contrast to a more conventional carrier vaccine (KLH). This approach directly addresses the need for a heat-stable and easily deliverable vaccine to improve equity in global vaccine coverage.
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http://dx.doi.org/10.1002/adhm.202001614DOI Listing
March 2021

Targeting HIV Env immunogens to B cell follicles in nonhuman primates through immune complex or protein nanoparticle formulations.

NPJ Vaccines 2020 Aug 5;5(1):72. Epub 2020 Aug 5.

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Following immunization, high-affinity antibody responses develop within germinal centers (GCs), specialized sites within follicles of the lymph node (LN) where B cells proliferate and undergo somatic hypermutation. Antigen availability within GCs is important, as B cells must acquire and present antigen to follicular helper T cells to drive this process. However, recombinant protein immunogens such as soluble human immunodeficiency virus (HIV) envelope (Env) trimers do not efficiently accumulate in follicles following traditional immunization. Here, we demonstrate two strategies to concentrate HIV Env immunogens in follicles, via the formation of immune complexes (ICs) or by employing self-assembling protein nanoparticles for multivalent display of Env antigens. Using rhesus macaques, we show that within a few days following immunization, free trimers were present in a diffuse pattern in draining LNs, while trimer ICs and Env nanoparticles accumulated in B cell follicles. Whole LN imaging strikingly revealed that ICs and trimer nanoparticles concentrated in as many as 500 follicles in a single LN within two days after immunization. Imaging of LNs collected seven days postimmunization showed that Env nanoparticles persisted on follicular dendritic cells in the light zone of nascent GCs. These findings suggest that the form of antigen administered in vaccination can dramatically impact localization in lymphoid tissues and provides a new rationale for the enhanced immune responses observed following immunization with ICs or nanoparticles.
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http://dx.doi.org/10.1038/s41541-020-00223-1DOI Listing
August 2020

Intranasal Subunit Vaccination Strategies Employing Nanomaterials and Biomaterials.

ACS Biomater Sci Eng 2020 Dec 16. Epub 2020 Dec 16.

Department of Biomedical Engineering, Duke University, 101 Science Drive, Durham, North Carolina 27708, United States.

Intranasal vaccines offer key advantages over traditional needle-based vaccines. They are simple to administer and painless and establish local immunity at mucosal surfaces. Owing to these advantages, they are particularly attractive for use in resource-limited locations of the world. Subunit vaccines also have advantages for global distribution, as they can be engineered to be more stable to fluctuations in environmental conditions than live-attenuated or inactivated vaccines, but they tend to be poorly immunogenic intranasally. Toward realizing the potential of intranasal subunit vaccination, biomaterial-based technologies are emerging. This review provides an overview of recent progress in the preclinical development of biomaterial-based intranasal vaccines against subunit antigens and should serve as an effective introduction to the current state of this exciting field. We provide a brief overview of the obstacles facing intranasal vaccine development and identify key design criteria for consideration when designing biomaterials for intranasal subunit vaccine delivery. Promising strategies are discussed across a wide array of biomaterial classes, with a focus on selected exemplary works that highlight the considerable potential of intranasal vaccines and the biomaterial-based technologies that enable them.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01291DOI Listing
December 2020

Targeting HIV Env immunogens to B cell follicles in nonhuman primates through immune complex or protein nanoparticle formulations.

NPJ Vaccines 2020 5;5:72. Epub 2020 Aug 5.

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 USA.

Following immunization, high-affinity antibody responses develop within germinal centers (GCs), specialized sites within follicles of the lymph node (LN) where B cells proliferate and undergo somatic hypermutation. Antigen availability within GCs is important, as B cells must acquire and present antigen to follicular helper T cells to drive this process. However, recombinant protein immunogens such as soluble human immunodeficiency virus (HIV) envelope (Env) trimers do not efficiently accumulate in follicles following traditional immunization. Here, we demonstrate two strategies to concentrate HIV Env immunogens in follicles, via the formation of immune complexes (ICs) or by employing self-assembling protein nanoparticles for multivalent display of Env antigens. Using rhesus macaques, we show that within a few days following immunization, free trimers were present in a diffuse pattern in draining LNs, while trimer ICs and Env nanoparticles accumulated in B cell follicles. Whole LN imaging strikingly revealed that ICs and trimer nanoparticles concentrated in as many as 500 follicles in a single LN within two days after immunization. Imaging of LNs collected seven days postimmunization showed that Env nanoparticles persisted on follicular dendritic cells in the light zone of nascent GCs. These findings suggest that the form of antigen administered in vaccination can dramatically impact localization in lymphoid tissues and provides a new rationale for the enhanced immune responses observed following immunization with ICs or nanoparticles.
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http://dx.doi.org/10.1038/s41541-020-00223-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406516PMC
August 2020

Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor.

Science 2019 07;365(6449):162-168

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Chimeric antigen receptor-T cell (CAR-T) therapy has been effective in the treatment of hematologic malignancies, but it has shown limited efficacy against solid tumors. Here we demonstrate an approach to enhancing CAR-T function in solid tumors by directly vaccine-boosting donor cells through their chimeric receptor in vivo. We designed amphiphile CAR-T ligands (amph-ligands) that, upon injection, trafficked to lymph nodes and decorated the surfaces of antigen-presenting cells, thereby priming CAR-Ts in the native lymph node microenvironment. Amph-ligand boosting triggered massive CAR-T expansion, increased donor cell polyfunctionality, and enhanced antitumor efficacy in multiple immunocompetent mouse tumor models. We demonstrate two approaches to generalizing this strategy to any chimeric antigen receptor, enabling this simple non-human leukocyte antigen-restricted approach to enhanced CAR-T functionality to be applied to existing CAR-T designs.
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http://dx.doi.org/10.1126/science.aav8692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800571PMC
July 2019

Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance.

Cell 2019 05 9;177(5):1153-1171.e28. Epub 2019 May 9.

Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address:

Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (T) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identified differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes.
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http://dx.doi.org/10.1016/j.cell.2019.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619430PMC
May 2019