Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | 121159 |
| Journal | Biomaterials |
| Volume | 278 |
| DOIs | |
| State | Published - Nov 2021 |
Funding
This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) [grant T32-HL007605]; the Canadian Institutes of Health Research [grant 201910MFE-430736-73744]; the National Institute of Allergy and Infectious Diseases (NIAID) [grant T32-AI007090]; and the Chicago Immunoengineering Innovation Center at the University of Chicago.We acknowledge helpful discussions with Patrick C. Wilson, Jenna J. Guthmiller, Anne I. Sperling, and Aaron Esser-Kahn (University of Chicago, Chicago, IL) and with Robert Baker and David Boltz (Illinois Institute of Technology Research Institute, Chicago, IL) that were instrumental to experimental planning and model development. We acknowledge Suzana Gomes and Tera Lavoie for technical assistance. Parts of this work were carried out at the Cytometry and Antibody Technology Core Facility (Cancer Center Support Grant P30CA014599), the Soft Matter Characterization Facility, the Mass Spectrometry Facility (NSF instrumentation grant CHE-1048528), the Nuclear Magnetic Resonance Facility, the Advanced Electron Microscopy Facility (RRID:SCR_019198), and the Human Immunologic Monitoring Facility (RRID:SCR_017916) at the University of Chicago. We would also like to thank the University of Chicago Animal Resources Center for help and guidance on animal work. We are grateful to the laboratory of Florian Krammer (Icahn School of Medicine at Mount Sinai, New York City, NY) for providing plasmids coding for the Spike RBD, produced with support from the NIH NIAID (Contract # HHSN272201400008C). We are also grateful to the groups of Jesse Bloom (Fred Hutchinson Cancer Research Center, Seattle, WA) and Ali Ellebedy (Washington University School of Medicine, St. Louis, MO) for contributing reagents via the NIH NIAID BEI Resources repository. This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) [grant T32-HL007605 ]; the Canadian Institutes of Health Research [grant 201910MFE-430736-73744 ]; the National Institute of Allergy and Infectious Diseases (NIAID) [grant T32-AI007090 ]; and the Chicago Immunoengineering Innovation Center at the University of Chicago . We acknowledge helpful discussions with Patrick C. Wilson, Jenna J. Guthmiller, Anne I. Sperling, and Aaron Esser-Kahn (University of Chicago, Chicago, IL) and with Robert Baker and David Boltz (Illinois Institute of Technology Research Institute, Chicago, IL) that were instrumental to experimental planning and model development. We acknowledge Suzana Gomes and Tera Lavoie for technical assistance. Parts of this work were carried out at the Cytometry and Antibody Technology Core Facility ( Cancer Center Support Grant P30CA014599 ), the Soft Matter Characterization Facility, the Mass Spectrometry Facility ( NSF instrumentation grant CHE-1048528 ), the Nuclear Magnetic Resonance Facility, the Advanced Electron Microscopy Facility (RRID: SCR_019198 ), and the Human Immunologic Monitoring Facility (RRID: SCR_017916 ) at the University of Chicago . We would also like to thank the University of Chicago Animal Resources Center for help and guidance on animal work. We are grateful to the laboratory of Florian Krammer ( Icahn School of Medicine at Mount Sinai , New York City, NY) for providing plasmids coding for the Spike RBD, produced with support from the NIH NIAID (Contract # HHSN272201400008C ). We are also grateful to the groups of Jesse Bloom (Fred Hutchinson Cancer Research Center, Seattle, WA) and Ali Ellebedy (Washington University School of Medicine, St. Louis, MO) for contributing reagents via the NIH NIAID BEI Resources repository.
Keywords
- Adjuvant
- COVID-19 vaccine
- Glycopolymers
- Polymer-protein conjugates
- Polymeric glyco-adjuvant
- Subunit vaccine formulation
ASJC Scopus subject areas
- Biophysics
- Bioengineering
- Ceramics and Composites
- Biomaterials
- Mechanics of Materials
