Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged in December 2019 and spread quickly causing the coronavirus disease 2019 (COVID-19) pandemic. Recent single cell RNA-Seq analyses have shown the presence of SARS-CoV-2 entry factors in the human corneal, limbal, and conjunctival superficial epithelium, leading to suggestions that the human ocular surface may serve as an additional entry gateway and infection hub for SARS-CoV-2. In this article, we review the ocular clinical presentations of COVID-19 and the features of the ocular surface that may underline the overall low ocular SARS-CoV-2 infection.We critically evaluate the studies performed in nonhuman primates, ex vivo organ culture ocular models, stem cell derived eye organoids and the differences in infection efficiency observed in different parts of human ocular surface epithelium. Finally, we highlight the additional work that needs to be carried out to understand the immune response of the ocular surface to SARS-CoV-2 infection, which can be translated into prophylactic treatments that may be applied to other organ systems.

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a pandemic and multiple vaccines have been developed and authorized for human use. While these vaccines reduce disease severity, they do not prevent infection allowing SARS-CoV-2 to continue to spread and evolve. To confer protection against infection and limit transmission, vaccines must be developed that induce mucosal immunity in the respiratory tract. Therefore, we performed proof-of-principle pre-clinical vaccine and challenge studies with a virus-particle mimicking intranasal vaccine against SARS-CoV-2. The vaccine candidate consisted of the self-assembling 60-subunit I3-01 protein scaffold covalently decorated with the SARS-CoV-2 receptor binding domain (RBD) using the SpyCatcher-SpyTag system. We verified the intended antigen display features by reconstructing the I3-01 scaffold to 3.4A using cryo-EM, and established RBD decoration through both SDS-PAGE and negative stain TEM. Using this RBD grafted SpyCage scaffold (RBD+SpyCage), we performed two vaccination studies in Syrian hamsters using an intranasal prime and boost vaccine regiment followed by SARS-CoV-2 challenge. The initial study focused on assessing the immunogenicity of RBD+SpyCage, which indicated that vaccination of hamsters induced a non-neutralizing antibody response that enhanced viral clearance but did not prevent infection. In an expanded study, we demonstrated that covalent bonding of RBD to the scaffold was required to induce an antibody response. Consistent with the initial study, animals vaccinated with RBD+SpyCage more rapidly cleared SARS-CoV-2 from both the upper and lower respiratory tract, whereas admixtures of SpyCage and RBD, or either component alone did not. These findings demonstrate the intranasal SpyCage vaccine platform can induce protection against SARS-CoV-2 and, with additional modifications to improve immunogenicity, is a versatile and adaptable system for the development of intranasal vaccines targeting respiratory pathogens.

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