Predicting the mutational drivers of future SARS-CoV-2 variants of concern

Abstract

SARS-CoV-2 evolution threatens vaccine- and natural infection-derived immunity, and the efficacy of therapeutic antibodies. Herein we sought to predict Spike amino acid changes that could contribute to future variants of concern. We tested the importance of features comprising epidemiology, evolution, immunology, and neural network-based protein sequence modeling. This resulted in identification of the primary biological drivers of SARS-CoV-2 intra-pandemic evolution. We found evidence that resistance to population-level host immunity has increasingly shaped SARS-CoV-2 evolution over time. We identified with high accuracy mutations that will spread, at up to four months in advance, across different phases of the pandemic. Behavior of the model was consistent with a plausible causal structure wherein epidemiological variables integrate the effects of diverse and shifting drivers of viral fitness. We applied our model to forecast mutations that will spread in the future, and characterize how these mutations affect the binding of therapeutic antibodies. These findings demonstrate that it is possible to forecast the driver mutations that could appear in emerging SARS-CoV-2 variants of concern. This modeling approach may be applied to any pathogen with genomic surveillance data, and so may address other rapidly evolving pathogens such as influenza, and unknown future pandemic viruses.

Emergence and Spread of a B.1.1.28-Derived P.6 Lineage with Q675H and Q677H Spike Mutations in Uruguay

“…Consistent with this notion, a recent study that used a reverse genetic system and primary human airway cultures identified mutation S:P681R as a significant determinant for enhanced viral replication fitness of the VOC Delta, and supported that Spike mutations that potentially affect furin cleavage efficiency must be closely monitored for future variant surveillance [85]. Notably, another study that developed an innovative model on epidemiological variables integrating the effect of Spike amino acid changes in viral fitness forecasted that mutations Q675H and Q677H could appear in emerging SARS-CoV-2 VOCs in the following months [86]. These observations underscore the importance of future experimental studies to assess the functional impact of Spike mutations Q675H and Q677H on virus infectivity and transmissibility.…”

Emergence and spread of a B.1.1.28-derived P.6 lineage with Q675H and Q677H Spike mutations in Uruguay

“…First, as explained above, they are in close proximity to the polybasic cleavage site at the S1/S2 boundary and the mutations are consistent with its potential functional relevance during cell entry. Second, a recent study that developed an innovative model on epidemiological variables integrating the effect of Spike amino acid changes in viral fitness, forecasted that both Q675H and Q677H could appear in emerging SARS-CoV-2 VOCs in the following months [60]. Third, and most importantly, convergent evolution is a hallmark of positive selection, and we identified the independent appearance of both Q675H and Q677H in 12 additional SARS-CoV-2 lineages.…”

Spatiotemporal dissemination pattern of SARS-CoV-2 B1.1.28-derived lineages introduced into Uruguay across its southeastern border with Brazil

“…The copyright holder for this preprint this version posted July 7, 2021. VOCs in the following months [41]. Although our phylogeographic analysis inferred the introduction of clade UY-II28 from Southeast Brazil into the Rocha department's capital, we could not rule out the existence of intermediate viral migration steps that were not All rights reserved.…”

“…The main clade was probably introduced from RS through Chuy, a Uruguayan-Brazilian twin-city, around late November 2020; while the second clade was probably introduced in the capital city of Rocha around early November 2020. The major B.1.1.28 clade detected in Rocha (UY-I28) displayed only one lineage-defining synonymous VOCs in the following months[41]. Although our phylogeographic analysis inferred the introduction of clade UY-II28 from Southeast Brazil into the Rocha department's capital, we could not rule out the existence of intermediate viral migration steps that were not recovered because of sampling gaps.…”