A cGAMP-containing hydrogel for prolonged SARS-CoV-2 RBD subunit vaccine exposure induces a broad and potent humoral response

  1. Volker Böhnert
  2. Emily C. Gale
  3. Lauren J. Lahey
  4. Jerry Yan
  5. Abigail E. Powell
  6. Ben S. Ou
  7. Jacqueline A. Carozza
  8. Lingyin Li
  9. Eric A. Appel

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Abstract

The receptor binding domain (RBD) of the SARS-CoV-2 virus spike protein has emerged as a promising target for generation of neutralizing antibodies. Although the RBD subunit is more stable than its encoding mRNA, RBD-based subunit vaccines have been hampered by RBD’s poor immunogenicity. We hypothesize that this limitation can be overcome by sustained co-administration with a more potent and optimized adjuvant than standard adjuvants. The endogenous innate immune second messenger, cGAMP, holds promise as potent activator of the anti-viral STING pathway. Unfortunately, delivery of cGAMP as a therapeutic exhibits poor performance due to poor pharmacokinetics and pharmacodynamics from rapid excretion and degradation by its hydrolase ENPP1. To overcome these limitations, we sought to create an artificial immunological niche enabling slow release of cGAMP and RBD to mimic natural infections in which immune activating molecules are co-localized with antigen. Specifically, we co-encapsulated cGAMP and RBD in an injectable polymer-nanoparticle (PNP) hydrogel. This cGAMP-adjuvanted hydrogel vaccine elicited more potent, durable, and broad antibody responses with improved neutralization as compared to dose-matched bolus controls and hydrogel-based vaccines lacking cGAMP. The cGAMP-adjuvanted hydrogel platform developed is suitable for delivery of other antigens and may provide enhanced immunity against a broad range of pathogens.

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  1. Version published to 10.1101/2021.07.03.451025v2 on bioRxiv
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    SciScore for 10.1101/2021.07.03.451025: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Both the RBD as an antigen and cGAMP as an adjuvant offer promising advantages, but each also possesses significant limitations related to ineffective delivery and poor localization within immune compartments. Here, we demonstrated that an injectable, self-assembled PNP hydrogel system simultaneously helps overcome delivery challenges posed by RBD and cGAMP, and that co-administration of these agents in this easily produced vaccine format leads to significant and functionally important increases in immunogenicity. While the importance of targeting the RBD is illustrated by the high fraction of neutralizing antibodies that target the RBD, we and others have now shown that engineering of delivery systems for the protein domain or its multimerization are required to generate appreciable anti-RBD antibody responses in vaccination.[8, 30, 51] For example, we have shown previously that delivery of subunit vaccines from a PNP hydrogel depot improves the humoral response compared to a dose-matched bolus control likely because prolonged antigen release better mimics the kinetics of antigen exposure occurring during a natural infection.[29, 30] A brief literature search showed that IC50 values from neutralization studies following immunization with our cGAMP hydrogel vaccine greatly exceeded the FDA “high titer” mark and exceeded IC50 values for both Spike- and RBD-encoding mRNA vaccines in mice. It is important to note that there were differences in dosing, timelines, and neutralizati...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT03172936CompletedStudy of the Safety and Efficacy of MIW815 With PDR001 in Pa…
    NCT03937141Active, not recruitingEfficacy and Safety Trial of ADU-S100 and Pembrolizumab in H…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2021.07.03.451025v1 on bioRxiv