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Principal Investigator: David Scott Wilson
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2022
Award: $204,688
Funding agency: National Institute of Biomedical Imaging and Bioengineering
1. ABSTRACT/SUMMARY
Given that the site of entry of SARS-CoV-2 is the respiratory mucosa, an effective vaccine for SARS-CoV-2 should
initiate both humoral and respiratory mucosal immune responses. Although an intranasal subunit vaccine would be an
ideal platform for SARS-CoV-2, transport across the nasal mucosa and a lack of safe and effective mucosal vaccine
adjuvants thwart the development of a clinically-viable intranasal subunit vaccine. We propose to develop an intranasal
vaccine composed of SARS-CoV-2 proteins conjugated to an immunostimulatory biomaterial that overcomes the
transport barriers of the nasal mucosa and thus induces protective mucosal and systemic immunity. Our platform is
composed of SARS-CoV-2 receptor-binding domain portion (RBD) conjugated to water-soluble polymers, termed
MPGAP, that are synthesized from monomers that bind nasal mucus, disrupt endothelial thigh junctions, and target and
activate antigen presenting cells (APCs). Thus, when administered intranasally, RBD- MPGAP conjugates should (1)
adhere to nasal mucus, increasing residency time at the nasal epithelium, (2) dismantle tight junctions, maximizing
paracellular transport to underlying APCs and nasal associated lymphoid tissue, (3) target conjugated RBD to and activate
APCs, eliciting APC-derived signals that activate T and B cells. By overcoming the biological barriers of the nasal
endothelium and targeting immunostimulatory factors to immune cells, RBD- MPGAP should induce protective mucosal
and systemic immunity in the absence of off-target effects. RBD-MPGAP conjugates will be produced, characterized, and
their ability to bind nasal mucus, enhance paracellular transport, and target and activate antigen presenting cells will be
tested in mice. The neutralizing antibody titer of serum and respiratory fluids from RBD-MPGAP-immunized mice will
be assessed via an in-vitro SARS-CoV-2 neutralization assay. Finally, the protective efficacy and durability of the
mucosal and systemic immunity elicited by internasal RBD-MPGAP will be investigated in a SARS-CoV-2 mouse model.
Completion of this project will validate the preclinical efficacy of an intranasal SARS-CoV-2 subunit vaccine and deliver
a platform that could combat numerous other respiratory infections, from seasonal influenza to the next respiratory viral
pandemic.
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