Epidemiology of Onchocerciasis

Abstract

<h3>Summary</h3> Rapid assessment of whether a pandemic pathogen may have increased transmissibility or be capable of evading existing vaccines and therapeutics is critical to mounting an effective public health response. Over the period of seven days, we utilized rapid computational prediction methods to evaluate potential public health implications of the emerging SARS-CoV-2 Omicron variant. Specifically, we modeled the structure of the Omicron variant, examined its interface with human angiotensin converting enzyme 2 (ACE-2) and evaluated the change in binding affinity between Omicron, ACE-2 and publicly known neutralizing antibodies. We also compared the Omicron variant to known Variants of Concern (VoC). Seven of the 15 Omicron mutations occurring in the spike protein receptor binding domain (RBD) occur at the ACE-2 cell receptor interface, and therefore may play a critical role in enhancing binding to ACE-2. Our estimates of Omicron RBD-ACE-2 binding affinities indicate that at least two of RBD mutations, Q493K/R and N501Y, contribute to enhanced ACE-2 binding, nearly doubling delta-delta-G (ddG) free energies calculated for other VoC’s. Binding affinity estimates also were calculated for 54 known neutralizing SARS-CoV-2 antibodies. Analysis of the results showed that Omicron substantially degrades binding for more than half of these neutralizing SARS-CoV-2 antibodies, and for roughly twice as many of the antibodies than the currently dominant Delta variant. This early study lends support to use of rapid computational risk assessments to inform public health decision-making while awaiting detailed experimental characterization and confirmation. <h3>Background</h3> The recently emerged Omicron variant of SARS-CoV-2 raised significant concerns on whether this variant, compared with the currently dominant Delta variant, will increase transmissibility and degrade immunity from vaccines or protection from neutralizing antibodies. This concern is primarily driven by an exceptionally large number of mutations present on the RBD, including several mutations that have not previously been observed in widely circulating variants. Stabilized expression of this substantially modified spike/RBD followed by in-vitro assessment of affinity and neutralization to antibodies and receptors is the gold standard investigational avenue, but takes several weeks even with the heightened urgency surrounding this variant. <h3>Objective</h3> On November 26, prior to experimental data/results being made public, we initiated an effort to apply our computational prediction platform to address the following questions. Does Omicron affect affinity to ACE-2, with implications for transmissibility and infectivity? Compared to previous SARS-CoV-2 variants, does Omicron affect/alter recognition by antibodies generated via vaccination or infection/exposure, with implications for adequacy of current countermeasures (monoclonal antibodies and vaccines)? Rapid availability of reliable predictions can help provide grounding data for decisions on preparedness and tailored response to emerging variants. <h3>Methods</h3> We have been developing computational methods to rapidly construct structural models of modified RBD’s and predict affinity to ACE-2 or neutralizing antibodies. A manuscript thoroughly describing our method, together with experimental validation demonstrating its accuracy, is in preparation and will be publicly available at a future date. The platform is designed to provide robust and reproducible computational predictions over a large number of binding complexes (multiple variant RBDs, multiple antibodies), with an interpretable confidence estimate, in a matter of days.