"How Omicron Evades Natural Immunity, Vaccination,
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Posted On: 12/21/2021 10:58:30 AM
"How Omicron Evades Natural Immunity, Vaccination, And Monoclonal Antibody Treatments" (part 3 of a series) was published on Dec. 17. The author is William Haseltine and this is his bio.
I am a scientist, businessman, author, and philanthropist. For nearly two decades, I was a professor at Harvard Medical School and Harvard School of Public Health where I founded two academic research departments, the Division of Biochemical Pharmacology and the Division of Human Retrovirology. I am perhaps most well known for my work on cancer, HIV/AIDS, genomics and, today, on COVID-19. My autobiography, My Lifelong Fight Against Disease, publishes this October. I am chair and president of ACCESS Health International, a nonprofit organization I founded that fosters innovative solutions to the greatest health challenges of our day. Each of my articles at Forbes.com will focus on a specific healthcare challenge and offer best practices and innovative solutions to overcome those challenges for the benefit of all.
Those who have time to read the entire article can find it here.
https://www.forbes.com/sites/williamhaseltine...e7245860e0
Now that the FDA appears to be working with us, I wonder if they might wind up taking some shortcuts if Omicron turns out to be more lethal than first thought. Here are some excerpts.
In a few short weeks, the COVID-19 virus variant Omicron has spread around the world. The incidence of new infections is rising rapidly, even in well-vaccinated populations and those previously infected by earlier variants of SARS-CoV-2. The epidemiologic evidence strongly points to a variant that is resistant to most if not all extant vaccines, and possibly many monoclonal antibodies treatments. Here we explore these concerns. This is the third in our series that outlines what we know about Omicron. We summarize the finding of recent experiments by Cameroni et al. in a bioRxiv preprint from December 14th.
The first question asked was how tightly the Omicron Spike (S) protein binds to the ACE2 receptor. The data is summarized in Figure 1. Cameroni et al. show that Omicron’s affinity for the ACE2 receptor is 2.5 times as great as that of the S protein from the original Wuhan isolate. Omicron binds to the receptor as well as the Beta variant, but not as well as Alpha, which binds ACE2 almost six times more tightly. The N501Y mutation in Omicron is universally observed to increase affinity roughly 6-fold, yet other mutations in key sites like K417N, Q493R, and G496S were shown by deep mutational scanning to decrease affinity. Increased affinity for the receptor may account, in part, for increased transmissibility, but that is clearly not the whole story as Omicron is much more transmissible than any previously isolates, including Alpha, Beta, Gamma, and Delta.
The next question they address is whether Omicron escapes neutralization by convalescent sera. Omicron strongly evades natural infection. Current data suggests that those who have been previously infected have little to no protection against Omicron infection. To analyze the degree to which the highly mutated Omicron escapes vaccine antibody neutralization, Cameroni et al. created Wuhan S and Omicron S pseudoviruses to test against a wide variety of existing vaccines. They tested the pseudoviruses against the sera from patients vaccinated with Moderna’s mRNA-1273, Pfizer’s BNT162b2, AstraZeneca’s AZD1222, J&J’s Ad26.COV2.S, Russia’s Sputnik-V, and Sinopharm’s BBIBP-CorV.
In the J&J cohort, no sera samples had neutralizing activity against Omicron. In the Sputnik cohort, only one in the cohort had mild neutralizing activity. And in the Sinopharm cohort, only three had mild neutralizing activity.
The data from figure 4 shows that fully-vaccinated sera with the Moderna vaccine saw a 33-fold drop in neutralization against Omicron, Pfizer a 44-fold drop, and AstraZeneca a 36-fold drop. Notably, Recently released data shows that sera from people who received the third dose lost almost ninety percent of its potency against Omicron after two weeks. After three months, most third-dose sera failed to neutralize at all. This data confirms the epidemiological observations that most fully doubly-vaccinated and triply-vaccinated individuals, including those with prior infection, are susceptible to infection by Omicron within three months of the last boost.
Of the eight approved or authorized antibodies, all but sotrovimab completely or almost completely lost their neutralizing activity against the Omicron pseudovirus. A cocktail of cilgavimab and tixagevimab had a reduced potency of 200-fold. Sotrovimab, conversely, shows a drop of 3-fold drop in neutralization potency.
In all, most monoclonal antibodies were completely ineffective against the Omicron variant. Some, such as sotrovimab, S2K146, and S2X324 retained neutralizing activity, but at a significant reduction. This points to the immune escape capabilities of Omicron via its distinctly mutated S protein and genome.
Conclusion
Many seem surprised at the ability of SARS-CoV-2 to mutate to increase resistance against convalescent sera, most vaccines, and most monoclonal antibodies. However, the surprise was unwarranted for those who realized that coronaviruses have evolved over many millions of years to reinfect hosts over time. Those previously infected with earlier strains of the virus, contrary to our assumptions earlier in the pandemic, are able to be reinfected with Omicron and strains to come.
We previously predicted that SARS-CoV-2 would persist, continue to vary, and evade our natural and adaptive immune responses. We have also learned that SARS-CoV-2 has the potential to become far more lethal than it is today. We reiterate that the sister of this virus, SARS-CoV, and its cousin, MERS-CoV, ranged between 10% and 30% lethality. This is presumably due to slight variations in the structural, nonstructural, and accessory proteins. We must be ever alert now and for many years in the future of the possibility of such changes and their consequences.
I am a scientist, businessman, author, and philanthropist. For nearly two decades, I was a professor at Harvard Medical School and Harvard School of Public Health where I founded two academic research departments, the Division of Biochemical Pharmacology and the Division of Human Retrovirology. I am perhaps most well known for my work on cancer, HIV/AIDS, genomics and, today, on COVID-19. My autobiography, My Lifelong Fight Against Disease, publishes this October. I am chair and president of ACCESS Health International, a nonprofit organization I founded that fosters innovative solutions to the greatest health challenges of our day. Each of my articles at Forbes.com will focus on a specific healthcare challenge and offer best practices and innovative solutions to overcome those challenges for the benefit of all.
Those who have time to read the entire article can find it here.
https://www.forbes.com/sites/williamhaseltine...e7245860e0
Now that the FDA appears to be working with us, I wonder if they might wind up taking some shortcuts if Omicron turns out to be more lethal than first thought. Here are some excerpts.
In a few short weeks, the COVID-19 virus variant Omicron has spread around the world. The incidence of new infections is rising rapidly, even in well-vaccinated populations and those previously infected by earlier variants of SARS-CoV-2. The epidemiologic evidence strongly points to a variant that is resistant to most if not all extant vaccines, and possibly many monoclonal antibodies treatments. Here we explore these concerns. This is the third in our series that outlines what we know about Omicron. We summarize the finding of recent experiments by Cameroni et al. in a bioRxiv preprint from December 14th.
The first question asked was how tightly the Omicron Spike (S) protein binds to the ACE2 receptor. The data is summarized in Figure 1. Cameroni et al. show that Omicron’s affinity for the ACE2 receptor is 2.5 times as great as that of the S protein from the original Wuhan isolate. Omicron binds to the receptor as well as the Beta variant, but not as well as Alpha, which binds ACE2 almost six times more tightly. The N501Y mutation in Omicron is universally observed to increase affinity roughly 6-fold, yet other mutations in key sites like K417N, Q493R, and G496S were shown by deep mutational scanning to decrease affinity. Increased affinity for the receptor may account, in part, for increased transmissibility, but that is clearly not the whole story as Omicron is much more transmissible than any previously isolates, including Alpha, Beta, Gamma, and Delta.
The next question they address is whether Omicron escapes neutralization by convalescent sera. Omicron strongly evades natural infection. Current data suggests that those who have been previously infected have little to no protection against Omicron infection. To analyze the degree to which the highly mutated Omicron escapes vaccine antibody neutralization, Cameroni et al. created Wuhan S and Omicron S pseudoviruses to test against a wide variety of existing vaccines. They tested the pseudoviruses against the sera from patients vaccinated with Moderna’s mRNA-1273, Pfizer’s BNT162b2, AstraZeneca’s AZD1222, J&J’s Ad26.COV2.S, Russia’s Sputnik-V, and Sinopharm’s BBIBP-CorV.
In the J&J cohort, no sera samples had neutralizing activity against Omicron. In the Sputnik cohort, only one in the cohort had mild neutralizing activity. And in the Sinopharm cohort, only three had mild neutralizing activity.
The data from figure 4 shows that fully-vaccinated sera with the Moderna vaccine saw a 33-fold drop in neutralization against Omicron, Pfizer a 44-fold drop, and AstraZeneca a 36-fold drop. Notably, Recently released data shows that sera from people who received the third dose lost almost ninety percent of its potency against Omicron after two weeks. After three months, most third-dose sera failed to neutralize at all. This data confirms the epidemiological observations that most fully doubly-vaccinated and triply-vaccinated individuals, including those with prior infection, are susceptible to infection by Omicron within three months of the last boost.
Of the eight approved or authorized antibodies, all but sotrovimab completely or almost completely lost their neutralizing activity against the Omicron pseudovirus. A cocktail of cilgavimab and tixagevimab had a reduced potency of 200-fold. Sotrovimab, conversely, shows a drop of 3-fold drop in neutralization potency.
In all, most monoclonal antibodies were completely ineffective against the Omicron variant. Some, such as sotrovimab, S2K146, and S2X324 retained neutralizing activity, but at a significant reduction. This points to the immune escape capabilities of Omicron via its distinctly mutated S protein and genome.
Conclusion
Many seem surprised at the ability of SARS-CoV-2 to mutate to increase resistance against convalescent sera, most vaccines, and most monoclonal antibodies. However, the surprise was unwarranted for those who realized that coronaviruses have evolved over many millions of years to reinfect hosts over time. Those previously infected with earlier strains of the virus, contrary to our assumptions earlier in the pandemic, are able to be reinfected with Omicron and strains to come.
We previously predicted that SARS-CoV-2 would persist, continue to vary, and evade our natural and adaptive immune responses. We have also learned that SARS-CoV-2 has the potential to become far more lethal than it is today. We reiterate that the sister of this virus, SARS-CoV, and its cousin, MERS-CoV, ranged between 10% and 30% lethality. This is presumably due to slight variations in the structural, nonstructural, and accessory proteins. We must be ever alert now and for many years in the future of the possibility of such changes and their consequences.
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