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Infection with SARS‐CoV‐2 elicits robust antibody responses in some patients, with a majority of the response directed at the receptor binding domain (RBD) of the spike surface glycoprotein. Remarkably, many patient‐derived antibodies that potently inhibit viral infection harbor few to no mutations from the germline, suggesting that naïve antibody libraries are a viable means for discovery of novel SARS‐CoV‐2 neutralizing antibodies. Here, we used a yeast surface‐display library of human naïve antibodies to isolate and characterize three novel neutralizing antibodies that target the RBD: one that blocks interaction with angiotensin‐converting enzyme 2 (ACE2), the human receptor for SARS‐CoV‐2, and two that target other epitopes on the RBD. These three antibodies neutralized SARS‐CoV‐2 spike‐pseudotyped lentivirus with IC₅₀values as low as 60 ng/ml in vitro. Using a biolayer interferometry‐based binding competition assay, we determined that these antibodies have distinct but overlapping epitopes with antibodies elicited during natural COVID‐19 infection. Taken together, these analyses highlight how in vitro selection of naïve antibodies can mimic the humoral response in vivo, yielding neutralizing antibodies and various epitopes that can be effectively targeted on the SARS‐CoV‐2 RBD.

The development of effective vaccines that can be rapidly manufactured and distributed worldwide is necessary to mitigate the devastating health and economic impacts of pandemics like COVID‐19. The receptor‐binding domain (RBD) of the SARS‐CoV‐2 spike protein, which mediates host cell entry of the virus, is an appealing antigen for subunit vaccines because it is efficient to manufacture, highly stable, and a target for neutralizing antibodies. Unfortunately, RBD is poorly immunogenic. While most subunit vaccines are commonly formulated with adjuvants to enhance their immunogenicity, clinically‐relevant adjuvants Alum, AddaVax, and CpG/Alum are found unable to elicit neutralizing responses following a prime‐boost immunization. Here, it has been shown that sustained delivery of an RBD subunit vaccine comprising CpG/Alum adjuvant in an injectable polymer‐nanoparticle (PNP) hydrogel elicited potent anti‐RBD and anti‐spike antibody titers, providing broader protection against SARS‐CoV‐2 variants of concern compared to bolus administration of the same vaccine and vaccines comprising other clinically‐relevant adjuvant systems. Notably, a SARS‐CoV‐2 spike‐pseudotyped lentivirus neutralization assay revealed that hydrogel‐based vaccines elicited potent neutralizing responses when bolus vaccines did not. Together, these results suggest that slow delivery of RBD subunit vaccines with PNP hydrogels can significantly enhance the immunogenicity of RBD and induce neutralizing humoral immunity.