This evidence synthesis has been compiled by members of the CITF Secretariat and does not necessarily represent the views of all CITF members.

By Varun Anipindi

The original Wuhan strain of SARS-CoV-2 has been evolving constantly since the onset of the COVID-19 pandemic. As with the case of many viruses, SARS-CoV-2 replicates numerous times within its host population. During the replication process, the new viral genome copies are checked by a self-encoded proof-reader that checks for mutations/modifications in the viral genome. However, the sheer scale of viral replication within the host population, together with error-prone proof-reading mechanisms, leads to the constant evolution of viral variants. While most mutations are irrelevant, occasionally some mutant strains have enhanced characteristics that enable them to prevail over others.

In a recent review by Plante J. A. et al, the authors discuss some of the factors that drive the emergence of variants of concern (VOCs)1. They highlighted 4 key factors: 1) Mutations that improve replication or transmission, 2) Mutations that can augment viral interaction with the host cell machinery after entry, 3) Selective pressure which iteratively eliminates other variants causing only those that can escape immunity to prevail, and 4) Iterative and additive changes from genetic drift induced by multiple singular mutations that may not immediately impact infection or transmission. The authors provide further insights which will be helpful for teams that are working on addressing concerns related to these SARS-CoV-2 VOCs.

Read more here.

Recently, the B.1.1.7, B1.351 and P1/P2 variants of SARS-CoV-2 that originated in the UK, South Africa and Brazil, respectively, have been found in a large number of other countries. The main characteristics of some of these VOC are increased transmission and virulence, alongside modifications to the S1 or Receptor Binding Domain (RBD) regions of the spike protein which can lead to immune escape from a variety of monoclonal antibodies that are currently approved for use in severe cases of COVID-19. Two research groups (Annavajhala M. K. et al2 and Lasek-Nesselquist E. et al3) have been surveying these variants in New York City and specifically tracing two key mutations (E848K and N501Y) in the viral sequences of infected individuals. What has emerged is the identification of a brand-new variant with an additional D235G substitution in the B.1.526 lineage that is rapidly spreading within the New York City metropolitan area. While these results are preliminary in nature, researchers have found that this variant (B.1.526) has increased within the population almost 26-fold in over a month and tends to lead to increased hospitalization in older patients, while hindering the effectiveness of monoclonal antibody-based therapies being used to treat individuals with severe disease.

Read pre-prints published by both Annavajhala M. K. et al and Lasek-Nesselquist E. et al.

While the emergence of these VOCs has presented new challenges to the current set of monoclonal antibodies and convalescent plasma-based therapies, scientists are actively working on the next generation of antibody therapies that can tackle these variants. Promising results from Wang et al. show four specific antibody clones isolated from the convalescent plasma of three early-VOC outbreak donors which target the RBD domain and demonstrate ultrapotent neutralization activity against nearly 12 separate VOCs including the highly virulent B.1.1.7 and B1.351 strains4. While further work is needed to determine the functional efficacy of these clones as potential treatments, these early findings suggest that when used in combination, these antibody clones are promising as a viable therapeutic option within the context of emerging VOCs.

Read pre-print here.

Tackling the emergence of variants remains a constantly moving target for both scientists and public health professionals. The same process of natural selection that has led to the evolution of life on earth is also responsible for emergence of variants that can potentially escape our COVID-19 mitigation strategies. However, it is encouraging that talented scientists around the world are working to meet this challenge and develop therapies that can help us end the pandemic.