Worrying new research shows that multiple BA.2 subvariants are surfacing across the United States, including mutations in the major protease (MPro) sites, lowering the antiviral effectiveness of Paxlovid’s primary pharmaceutical ingredient, Nirmatrelvir.

H164N, G15S, and T135I are examples of NSP5 or MPro mutations.

In places like Washington, Idaho, California, North Carolina, Colorado, Florida, Georgia, Indiana, Texas, Kentucky, North Dakota, Oregon, Pennsylvania, Tennessee, Utah, and Wisconsin, genomic sequencing data shows that a number of subvariants spotting these variants are forming.

Due to a lack of appropriate surveillance in many states and the current lenient attitude in the United States toward COVID-19, it is likely that there are more than these 16 states where Paxlovid drug resistance subvariants are forming, and the numbers could be much higher.

Scientists aren’t clear if the development of these subvariants contributed to the high rate of SARS-CoV-2 rebound in many Paxlovid patients.

When Paxlovid and Molnupiravir were approved to treat COVID-19, many studies cautioned that drug resistance variants will emerge and that these medications would be promoting mutations and evolutions in the many circulating versions.

In addition to making the new subvariants drug-resistant to Paxlovid and Molnupiravir, the changes to the MPro/NSP5 proteins caused by these drug-driven mutations raise concerns because they could also render many other compounds, such as repurposed drugs, phytochemicals, and small bioactive molecules, which have shown antiviral activity against SARS-CoV-2 and are currently being investigated in various clinical trials, useless.

According to research that was presented on the website of the United States Food and Drug Administration (FDA), the following Mpro amino acid substitutions were associated with decreased nirmatrelvir activity (Ki values that were at least threefold higher): G15S (4.4-fold), T135I (3.5-fold), S144A (91.9-fold), H164N (6.4-fold), H172Y (233-fold), Q189K (65.4-fold), and D248E. (3.7-fold). G15S is found in the Lambda variant, which did not show lower nirmatrelvir susceptibility in cell culture (compared to USA-WA1/2020). ^{1, 2}

The use of Paxlovid and Molnupiravir is also thought to be causing the appearance of other mutations on BA.2 variants such as NSP5 T21I, NSP5 T24I, NSP5 K90R, NSP5 P108S, NSP5 P132H, NSP5 P241L, and NSP5 H246N.

The discovery of effective antivirals and treatments could be hampered by such a dramatic alteration in the MPro/NSP5 proteins.

Importantly, people must recognize that many treatment protocols that have been advocated by various groups and individuals since the outbreak began are no longer effective against the various emerging BA.2 subvariants, BA.4 and BA.5 variants, as well as the new third and fourth generation Delta subvariants.

With many people in denial and many more assuming that the threat from SARS-CoV-2 has passed, and assuming that the newer variants are becoming mild (mild only upon infection, but we have no idea about their pathogenesis or how they affect the human host in the mid-term and long-term.), the relaxation of COVID-19 measures and travel restrictions, combined with the kinetics of the pandemic, a more catastrophic scenario is likely to emerge around the world.

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