ABSTRACT
Background: As SARS-CoV-2 continues to mutate into Variants of Concern (VOC), there is growing and urgent need to develop effective antivirals to combat COVID-19. Monoclonal antibodies developed earlier are no longer capable of effectively neutralizing currently active VOCs. This report describes the design of variant-agnostic chimeric molecules consisting of an Angiotensin-Converting Enzyme 2 (ACE-2) domain mutated to retain ultrahigh affinity binding to a wide variety of SARS-CoV-2 variants, coupled to an Fc-silent immunoglobulin domain that eliminates antibody-dependent enhancement and extends biological half-life. Methods: Molecular modeling, Surrogate Viral Neutralization tests (sVNTs) and infection studies of human airway organoid cultures were performed with synthetic chimeras, SARS-CoV-2 spike protein mimics and SARS-CoV-2 Omicron variants B.1.1.214, BA.1, BA.2 and BA.5. Results: ACE-2 mutations L27, V34 and E90 resulted in ultrahigh affinity binding of the LVE-ACE-2 domain to the widest variety of VOCs, with KDs of 93 pM and 73 pM for binding to the Alpha B1.1.7 and Omicron B.1.1.529 variants, and notably, 78fM, 133fM and 1.81pM affinities to the Omicron BA.2, BA2.75 and BQ.1.1 subvariants, respectively. sVNT assays revealed titers of ≥4.9 ng/ml, for neutralization of recombinant viral proteins corresponding to the Alpha, Delta and Omicron variants. The values above were obtained with LVE-ACE-2/mAB chimeras containing the FcRn-binding Y-T-E sequence which extends biological half-life 3-4-fold. Conclusions: The ACE-2-mutant/Fc silent fusion proteins described have ultrahigh affinity to a wide variety of SARS-CoV-2 variants including Omicron. It is proposed that these chimeric ACE-2/mABs will constitute variant-agnostic and cost-effective prophylactics against SARS-CoV-2, particularly when administered nasally.
ABSTRACT
BACKGROUND: The COVID-19 pandemic has rapidly affected all facets of everyday life including the practice of medicine. Hospital systems and medical practices have evolved to protect patients, physicians, and staff and conserve personal protective equipment and resources. Orthopaedic practices have been specifically affected by social distancing and stay at home guidelines, limiting in-office practice and elective surgery restrictions. This, in turn, has had an effect on resident education. Previous literature has been published regarding how academic programs have adjusted to these changes. However, the effects on smaller orthopaedic residencies with nonacademic faculty has not been discussed. The orthopaedic residency at Baylor University Medical Center of Dallas is a fifteen-resident program with a combination of hospital employed and private practice faculty. We adjusted our resident education in mid-March 2020 to keep residents safe while trying to maximize surgical and clinical education and outside research. GOALS: Our goals were to come up with a plan allowed for continuing high-level patient care and resident education while protecting residents and limiting burnout. MODEL: We devised a four-team system with five-day call periods. Interactions between teams were strictly minimized. We also moved to a web-based academic curriculum and devised a system for safe resident participation in surgical cases. The model has been adjusted based on attending and resident feedback. CONCLUSION: Until we develop effective treatments or vaccination for COVID-19, there is a possibility that it will be an ongoing threat. Resident education must also adapt to the changing environment while continuing to provide residents safe opportunities for patient care, didactic education, and research. We believe we have come up with a sustainable, adaptable model for resident education during this challenging time.