A Dark Horse In The Covid Pandemic

getty Far from ending, the Covid pandemic seems to be accelerating with new variants. The BA.5 variant is spreading rapidly in Europe and North America, potentially infecting as many or more people as the original Omicron virus from which it originated. A second variant, BA.2.75, was identified in India and is growing rapidly. We have previously described BA.4 and BA.5. here, we focus on the novel BA.2.75. The Omicron BA.1 variant emerged in late 2021 with significant genetic and virological differences. BA.1 was quickly followed by the genetically distinct progeny BA.2. Figure 1 shows the initial rise of BA.1, quickly followed by BA.2. These accounted for the bulk of cases during the winter months of early 2022, when confirmed cases in the United States peaked at about 1 million per day. BA.4 and BA.5, which are very similar, derive from BA.2, as does BA.2.75, although independently. There is no relation between the Omicron BA.1 and the other major variants, Alpha, Beta, Gamma, Delta, etc. BA.4/BA.5 is the dominant strain of Covid-19 today and we believe that BA.2.75 may join them. FIGURE 1: BA.2.75 arose independently from BA.2, which differs significantly from BA.4 and BA.5. ACCESS Health International FIGURE 2: Cases in the United States identified by variant type. Stebbing Later Omicron variants, such as the currently dominant strains BA.4 and BA.5, appear capable of reinfecting those previously infected with an older strain. Those infected with BA.1 were susceptible to BA.2 and so on. One report indicated that BA.5 was between 14.3 and 16.8 times more resistant to the antibody treatments Evusheld and Sotrovimab than previous variants. This resistance, in addition to novel mutations, is likely related to sensitivity to a membrane protease, TMPRSS2, associated with cell membrane infectivity. BA.5 is more sensitive to the TMPRSS2 inhibitor Nafamostat, which means that BA.5 is slightly less virulent than BA.1 and BA.2, but could be more virulent and immunogenic, similar to 2021 Delta variant. FIGURE 3: (A) Shift in the linear regression between viral infectivity and diagnostic PCR Ct values ​​… [+] gives a measure of TMPRSS2 usage by single variants (BD) Primary nasopharyngeal swabs were used to inoculate the HAT-24 cell line. Cultures of (B) AY39.1 (one of the last detected Delta lines), (C) BA.2 and (D) BA.5 imaged 72 h post-infection. (D) Infectivity for BA.2 and BA.5. (F) Virion particle measurements for three early clade variants (A.2.2, Beta and Delta) and three Omicron sub-lines (G) Schematic showing the effect of the TMPRSS2 inhibitor Nafamostat on viral entry into the cell membrane. (H) The efficiency of TMPRSS2 usage by the virus. Aggarwal et al. The latest in the line of Omicron variants is BA.2.75, which has a distinct set of Spike mutations in addition to those found in BA.2, BA.4, BA.5 and other mutations outside of the Spike protein, indicating that it was originating independently from the NE.2. BA.4 and BA.5 are very similar, differing by only a few mutations in the structural proteins N and M, the nonstructural protein NSP4, and the accessory proteins Orf6 and Orf7b, as described in a previous discussion (Figure 3). These differences appear to give BA.5 a breeding advantage, outperforming BA.4 in North America and Europe (Figure 2). Both silent and amino acid-altering mutations in the Orf1ab replication complex, structural proteins and accessory genes can increase the virulence of SARS-CoV-2. It remains to be determined which mutation gives BA.5 the reproductive advantage it possesses. FIGURE 4: Non-Spike Protein Mutations in BA.4 and BA.5 Dr. Tulio del Olivera BA.2.75 is still very new. It was recently discovered in India, followed by ten countries soon after. The World Health Organization has already issued a warning about BA.2.75 and continues to monitor the variant as it spreads to more regions of the globe. While confirmed cases due to BA.2.75 are relatively low, the numbers are expected to increase in the coming weeks. Not only is BA.2.75 a derivative of BA.2, but it is different from BA.4 and BA.5. FIGURE 5: Venn diagram comparison of BA.4/BA.5 versus BA.2.75 mutants. The ones on the left are… [+] unique to BA.4 and/or BA.5, those on the right are unique to BA.2.75, and those in the middle are shared between the two strains. ACCESS Health International Spike is the most heavily mutated protein in the Omicron family of variants. This pattern applies with BA.2.75. There are 36 mutated amino acids in the BA.2.75 Spike protein. Some early variants, such as Alpha, did not even carry 36 amino acid mutations in their entire genome. BA.2.75 has this amount in the Spike protein, which represents about 10% of the SARS-CoV-2 genome. FIGURE 6: BA.2.75 spike protein mutations. The ones in red are in NE.2.75. The ones in blue are… [+] unique to BA.2.75, meaning not in BA.2. The single mutation highlighted in green indicates that the position reverted from Q493R to Q493 in BA.2.75. The ones in black are not found in BA.2.75 or BA.2 but are found in other Omicron strains. ACCESS Health International Unique mutations of the BA.2.75 spike protein are isolated in the N-terminus and receptor-binding domains. These are regularly the most heavily mutated regions of the virus, as they are typical targets for neutralizing antibodies derived from infection, vaccines, and monoclonal therapies, meaning that mutations may allow the virus to overcome neutralization. These regions also play an important role in the transmissibility of the virus, telling how later variants become more virulent. New additions fall into two categories: new mutations and reversals. We find only one reversal in BA.2.75, which is Q493. In BA.2, this position was mutated from glutamine to arginine (Q493R), a common mutation in circulating variants throughout the pandemic. Inversions are uncommon, as a mutation often confers some virological advantage over the original amino acid. However, this inversion can complementarily interact with a new single mutation to provide a more significant advantage than Q493R could have on its own. In addition to the inversion, there are eight mutations in Spike BA.2.75 that are unique to BA.2. Furthermore, all but one of these eight mutations (K147E, W152R, F157L, I210V, G257S, G339H, and N460K) are uncommon in any previous variant of concern or interest. We note that F157L was previously detected in a small African strain A.23.1. The mutations occur at position I210 in the African A.30 and French B.1.640 strains but in different mutations (I210N and I210T, respectively). Furthermore, the W152 locus has been mutated in the 2021 Epsilon strain, but to W152C. To have such unique mutations at this stage of the pandemic, when the virus has mutated into hundreds, even thousands of competing strains, is surprising. These mutations likely have health officials on high alert, as a wealth of new mutations could indicate increased transmissibility or immune evasion if the variant catches fire like its predecessor. The new line also has five new additions in addition to the Spike protein. Four are in the Orf1ab replication-transcription complex and the last one is in the Envelope protein. FIGURE 7: BA.2.75 mutations outside the Spike protein. The ones in red are in NE.2.75. They in… [+] Blue is unique to BA.2.75, meaning it is not in BA.2. The ones in black are not found in BA.2.75 or BA.2 but are found in other Omicron strains. ACCESS Health International Two of the unique mutations, S403L and P822S, are located in NSP3. This protein is involved in the formation of the double membrane vesicle replication compartment structure. It also inhibits interferon activity by directly cleaving IRF3 and antagonizing MDA5 activation. These mutations could therefore be involved in viral replication and immune evasion activities. We additionally note N118S in NSP8, G671S in NSP12 and T11A in the Envelope protein. NSP12 is the RNA polymerase that drives viral replication and transcription, while NSP8 is a structural cofactor for this machinery. Envelope is involved in virus assembly, budding and viral porin activity. More research on these unique mutations is needed to determine their exact benefits, but they are likely involved in these processes. You can read more about the functions of each protein in our book Natural Immunity. There may be several mutations that do not change amino acids in the coding sequence, known as synonymous mutations, but we do not have access to them at this time. Even as we write this article, the Omicron family is constantly evolving. In addition to the BA.2.75, recent reports from India suggest that there are companion series BA.2.74 and BA.2.76 being released at the same time as the BA.2.75. At present, the exact sequences are not available for viewing in the GISAID SARS-CoV-2 database, although the researchers suggest that they share the same Spike protein, implying that the differences lie outside the Spike, just as BA.2.75 differs from previous variations. In summary, having just recovered from the first Omicron wave of BA.1 and BA.2 at the beginning of the year, as well as the BA.2.12.1 wave in the United States and elsewhere, the world now faces two additional variants, which can individually or collectively surpass the first wave in size. In the UK outbreak alone, infections have increased by several hundred thousand in the previous weeks due to the new strains. If the US were to experience similar increases, daily rates could climb into the millions, surpassing the peak of the Omicron wave in mid-January. The impact of BA.5 and BA.2.75 on health outcomes, hospitalization and death remains to be seen. All countries except China have abandoned public mitigation measures, meaning that Covid safety is now the responsibility of the individual, which is a sad state of affairs given the ongoing…