Many faces in shades of color
This is part of an ongoing series describing Antiviral antibodies to prevent and treat SARS-CoV-2 infection. In this series, we will discuss the fundamental nature of virus evolution, how SARS-CoV-2 has mutated to evade neutralizing antibodies, and our recent attempts to combat these mutations with more modern and improved antibodies.
The most recent versions of Omicron that take charge of the recent new cases are BA.4, BA.5 and BA 2.75. Since its discovery in late 2021, dozens of variants of the original Omicron strain have caused hundreds of millions of infections. Each strain carries a slightly different genetic sequence due to mutations that have evolved over time. These mutations are sometimes nonsensical but often affect key viral characteristics including infection and immune evasion.
Omicron BA.1 contains 30 spike protein spikes alone. Later versions of Omicron expand on this wide range. These mutations were a significant factor in the rapid rise of omicron last winter, infecting nearly one million people in the United States daily at its peak. These mutations increase transmission of the virus in the population, whether vaccinated or not, by more than tenfold compared to the original Wuhan strain.
Figure 1: Cryo-EM structure of omicron protein BA.1. (a) a schematic diagram illustrating … [+]
Of note, Omicron has a number of mutations outside of the spike protein as well. These influence viral properties including replication efficiency, pathogenesis, and virulence. There are 19 mutations in non-Spike proteins throughout the genome, including Orf1a, Orf1b, E, M, Orf8, and N.
Figure 2: BA.1 non-spike mutations.
On top of its infection, Omicron evasion of natural immunity, vaccine-induced immunity, and monoclonal antibody immunity lie particularly in this discussion. Monoclonal antibodies target specific structures, often in the spike protein. In the first year of the epidemic, scientists made antibodies to the original Wuhan version of SARS-CoV-2. However, with each Spike mutation, the Spike’s structure changes slightly.
Think of a key in the lock. They made a key for the lock, but the lock has changed its shape in the meantime. Then the scientists created a new key for the new lock, but the lock was constantly changing, and the cat-and-mouse game continued.
in early time study On the neutralization of Omicron BA.1 by several approved and current monoclonal antibodies, 26 of the 29 were found to have lost some or all of the neutralizing potency against the new strain. It is possible that the later Omicron sub-variants may have increased immune escape and may reduce the efficacy of these antibodies further.
Equivalent efficiency appears to be getting worse as Omicron evolves into more mutated strains such as the newer BA.4 and BA.5. These later variants are more mutated in the receptor-binding domain than BA.1, which means that antibodies targeting the receptor-binding domain will have a much tougher time binding and neutralizing the new variants.
Figure 3: Omicron BA.1, BA.4, BA.5 and BA 2.75 compared to spike proteins.
The persistence of the mutation in Omicron also leads to a reduced efficacy of the vaccine against subsequent strains. For example, three doses of Pfizer’s vaccine are about three times less effective against BA.4 or BA.5 than it is against BA.1, BA.2 or BA.3.
Figure 4: IC50 values for viruses indicated using serum obtained from vaccines after 4 weeks … [+]
All is not lost. Among those that could neutralize Omicron was 35B5, a potent, broadly neutralizing monoclonal antibody effective against all known variants. Instead of making a new key for the lock, the 35B5 essentially unlocks the door. This antibody targets specific amino acids in the N-terminal domain of Spike that are non-regularly mutagenic. This indicates that the unstimulated structure at those loci is critical for virus function, such as N165 and N234, which together act as a molecular switch for spike up-and-down changes.
By targeting non-mutated positions not only in the Omicron but in all variants, the 35B5 breaks the door lock, making it future-proof against the more mutated variants that may come our way in the coming months or years. In our opinion, all monoclonal antibodies should follow a broad neutralization strategy. Three recently detected antibodies showed promising early results in the laboratory tests.
The first two, Cv2.1169 and Cv2.3194, have been isolated by researchers at the Pasteur Institute in recent months. Both antibodies are noteworthy because they cross over with both BA.1 and BA.2, indicating an extensive network of neutralization. Cv2.1169, in particular, has shown therapeutic efficacy in animal models as well.
The third, SP1-77, was recently detailed by a team of researchers at Harvard Medical School and Duke University School of Medicine. This antibody also neutralizes BA.1 and BA.2, as well as all other variants of concern. The unique antibody was generated by our humanized mouse model and prevents membrane fusion rather than RBD binding. The more weapons we have in our arsenal, the better.
We will also describe the latest in the Omicron family: BA.2.75. You may find descriptions of other notable Omicron family members, such as BA.4, BA.5, and BA.2.12.1 in previous articles.
