COVID-19 Today
December 27, 2021: Let’s dig into the science!
Below are five articles that stand out as being among the most powerful regarding COVID-19 this week.
Let’s get to it!
Nature Immunology volume 23, pages40–49 (2022)
New data show that, compared with adults, children infected by SARS-CoV-2 preferentially activate pre-existing immunity to endemic common-cold coronaviruses that are cross-reactive with SARS-CoV-2.
This study quantitatively profiles the antibody and T cell immune responses to SARS-CoV-2 in a cohort of 91 children and 154 adults — one of the largest cohorts examined to date — who had mild or asymptomatic disease in the United Kingdom during the latter half of 2020.
Highlights:
Children mount exceptional immune responses, when compared to adults. The child’s pre-existing immunity is cross-reactive with pre-pandemic ‘common cold’ human coronaviruses as well as SARS-CoV-2. These enhanced immune responses likely derive from prior common cold exposures. Therefore, children generate robust, cross-reactive and sustained immune responses to SARS-CoV-2 with focused specificity for the spike protein.
One issue with this study is that it is profiling the original variant of SARS-CoV-2, not Delta or the new Omicron variant. Although the immune profile observed by children to Delta and Omicron imply that this immune response profile is most likely unchanged.
The CDC estimates 146.6 million cases of COVID-19, that is 45% of the US population. Unfortunately, their page is grossly outdated -with the last update being October 2, 2021. Assuming a linear curve, that would mean another 20 million have been infected since that date, bringing the total to 166 million. This is basically 50% of the US population.
Ergo: at least 50% of children have had SARS-CoV-2. But even if they haven’t had COVID-19 the child’s pre-existing immunity to the common cold will provide more than adequate protection from COVID-19 disease.
Evolution of enhanced innate immune evasion by SARS-CoV-2
Nature 2021 Dec 23. doi: 10.1038/s41586-021-04352-y. Online ahead of print.
From the Abstract:
“Emergence of SARS-CoV-2 variants of concern (VOCs) suggests viral adaptation to enhance human-to-human transmission. Although much effort has focused on characterization of spike changes in VOCs, mutations outside spike likely contribute to adaptation. Here we used unbiased abundance proteomics, phosphoproteomics, RNAseq and viral replication assays to show that isolates of the Alpha (B.1.1.7) variant3 more effectively suppress innate immune responses in airway epithelial cells, compared to first wave isolates. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful Alpha transmission, and may increase in vivo replication and duration of infection. The importance of mutations outside Spike in adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the Delta and Omicron N/Orf9b regulatory regions.”
Why is this important. This study not only emphasizes that Omicron increases in-vivo replication by more effectively suppressing innate immune* responses in airway epithelial cells, compared to first wave variants and that Omicron also increases duration of infection. Increased replication (more virus in the body) and duration of infection means that for a longer time, more virus can be spread to others. So, more “viral load” being produced for a longer time means higher transmissibility. This peer reviewed study confirms what other, very early studies have hypothesized about Omicron.
*Innate immunity: Innate immunity is an evolutionary old defense system that generates a fast inflammatory response that is generic to all types of pathogens or tissue damages and does not confer immune memory to the host. The innate immune system is defined as the first line of host defense against invasive pathogens by discrimination of “non-self” versus “self.” Virtually all cells can contribute to innate immunity by producing certain proteins, called cytokines that are secreted by cells to regulate the immune system. However, Macrophages, DCs, and natural killer cells are the main immune cell types responsible for innate responses.
Omicron: A Drug Developer's Perspective
Emerg Microbes Infect 2021 Dec 24;1-10. doi: 10.1080/22221751.2021.2023330. Online ahead of print.
This is an interesting paper. The authors tabulate the 35 spike mutations in Omicron, listing out the mechanisms of action for each mutation as determined via computer modelling. This exercise gave insights into what Omicron might be capable of. They then tried to use this data to integrate new perspectives on future approaches in combating SARS-CoV-2.
The authors write that Omicron appears to have learned from the older variants:
“Only 6 of its 61 mutations are unique, the rest already existed in the sequenced genomic pool of SARS-CoV-2, including 20 very abundant convergent mutations that Omicron shares with other prominent variants. Notably, the Omicron spike protein contains 15 convergent mutations, all of which confer an advantage either in immune evasion or in transmissibility.”
The authors then reviewed recent literature. They write that Omicron significantly escapes the two-dose vaccine regime, ranging from complete loss to 33- to 44-fold* reduction of neutralizing activities and that the 2-dose vaccination and the boosted vaccine(s) regime quickly loses protection against delta.
The authors hypothesize that future COVID19 therapies should ideally meet three criteria:
1.) it should have high potency and resistance barrier;
2.) it should be effective at reducing viral replication and minimize viral spreading;
3.) it should be effective against all SARS-CoV-2 variants, including the future ones, and avoid introducing additional selective pressure towards resistant variants.
The authors conclude that the prospect of controlling spread of Omicron and the future SARS-CoV-2 variants by vaccination is not viable, especially if the virus continues to enhance its abilities in immune evasion and transmissibility.
*Fold: A fold change is basically a ratio. It indicates the number of times something has changed in comparison to an original amount. For quantities A and B, the fold change of B with respect to A is B/A. For example, A twofold increase indicates that an amount doubled. Fold change is useful in examining data for increases and decreases.
Omicron overpowers key COVID antibody treatments in early tests
Nature, News. Dec 21, 2021
News: preliminary experiments suggest that most of the antibody treatments for the disease are powerless against Omicron.
Doctors use artificial versions of natural antibodies to stave off severe COVID-19 in high-risk people who are infected with the coronavirus. But a slew of (pre-print) publications posted on preprint servers report laboratory evidence that Omicron is totally or partially resistant to all currently available treatments based on these monoclonal antibodies.
The preprint reports that only two antibodies show strong evidence of retaining some ability to thwart the variant: sotrovimab, developed by Vir Biotechnology in San Francisco, California, and GSK, headquartered in London; and DXP-604, which is undergoing clinical trials in China and was developed by BeiGene and Singlomics, both based in Beijing.
US health officials have said they will ration sotrovimab. It is being allotted to states on the basis of numbers of infections and hospitalizations as well as the prevalence of Omicron. Other countries either have no product or face severe shortages of sotrovimab.
BMJ 2021; 375 doi: https://doi.org/10.1136/bmj.n3151 (Published 24 December 2021)
Highlights:
Using a small sample size which excluded people with previous COVID-19 infections, data from the UK shows that someone infected with the omicron variant of SARS-CoV-2 is estimated to be between 31% and 45% less likely to attend emergency care than if they had been infected with the delta variant and 50-70% less likely to be admitted to hospital, analysis by the UK Health Security Agency has shown.
Due to increased transmission, the number of people who end up in the hospital at once could be huge.
The analysis also found that omicron was more likely than previous variants to reinfect people who have previously had covid-19, with 9.5% of those infected having a history of past infection. This did not include asymptomatic prior infections, meaning they are not reported in the numbers.
Looking at vaccine efficacy, the report said that the data are continuing to show lower effectiveness against symptomatic omicron. Evidence indicates that although two doses of vaccine are less effective against omicron than against the previously dominant delta variant, a booster dose improves protection. But this extra protection may wane more rapidly against omicron than delta, being about 15-25% lower from 10 weeks after the booster.
It’s still too early to estimate vaccine effectiveness against hospital admissions.
The agency’s findings are consistent with three recent studies, not yet peer reviewed, from researchers in England, Scotland, and South Africa, which all concluded that omicron carried a lower risk of hospital admission than delta.
Even though this study is not about Omicron, is not yet peer reviewed and is four months old, I believe it is one of the most important studies recently published. The impact of COVID-19 policies on children is one of the most important issues not being reported on.
Medrxiv -preprint published in August, 2021 doi: https://doi.org/10.1101/2021.08.10.21261846
Leveraging a large on-going longitudinal study of child neurodevelopment, the study examined general childhood cognitive scores in 2020 and 2021 vs. the preceding decade, 2011-2019.
· Children born during the pandemic have significantly reduced verbal, motor, and overall cognitive performance compared to children born pre-pandemic.
· Males and children in lower socioeconomic families have been most affected.
Results of this study highlight that even in the absence of direct SARS-CoV-2 infection and COVID-19 illness, the environmental changes associated COVID-19 pandemic is significantly and negatively affecting infant and child development.
The mechanisms of action of ivermectin against SARS-CoV-2—an extensive review
The Journal of Antibiotics, Published 21 December 2021
Previously retracted 15 June 2021, this extensive review has now been permitted to be published. Includes both a table of studies addressing probable mechanisms of action of ivermectin against SARS-CoV-2 as well as a summary graphic. The 72 cited references can be downloaded here.
The authors conclude that “We have summarized published results on the inhibition of multiple viral and host targets that could be involved in SARS-CoV-2 replication and the disease COVID-19. Although multiple antiviral and host target activities have been reported for ivermectin in SARS-CoV-2 and COVID-19, it is still unclear if any of these activities will play a role in the prevention and treatment of the disease. The controlled clinical trials that are underway will reveal if these activities will translate into clinical efficacy.”
Risk of myocarditis following sequential COVID-19 vaccinations by age and sex
MedRx (preprint, not peer reviewed): https://doi.org/10.1101/2021.12.23.21268276
“In an updated self-controlled case series analysis of 42,200,614 people aged 13 years or more, we evaluate the association between COVID-19 vaccination and myocarditis, stratified by age and sex, including 10,978,507 people receiving a third vaccine dose. Myocarditis risk was increased during 1-28 days following a third dose of BNT162b2 (IRR 2.02, 95%CI 1.40, 2.91). Associations were strongest in males younger than 40 years for all vaccine types with an additional 3 (95%CI 1, 5) and 12 (95% CI 1,17) events per million estimated in the 1-28 days following a first dose of BNT162b2 and mRNA-1273, respectively; 14 (95%CI 8, 17), 12 (95%CI 1, 7) and 101 (95%CI 95, 104) additional events following a second dose of ChAdOx1, BNT162b2 and mRNA-1273, respectively; and 13 (95%CI 7, 15) additional events following a third dose of BNT162b2, compared with 7 (95%CI 2, 11) additional events following COVID-19 infection. An association between COVID-19 infection and myocarditis was observed in all ages for both sexes but was substantially higher in those older than 40 years.”
“In summary, the risk of hospital admission or death from myocarditis is greater following COVID-19 infection than following vaccination and remains modest following sequential doses of mRNA vaccine including a third booster dose of BNT162b in the overall population. However, the risk of myocarditis following vaccination is consistently higher in younger males, particularly following a second dose of RNA mRNA-1273 vaccine.”
SARS-CoV-2 spreads through cell-to-cell transmission
PNAS January 4, 2022 119 (1) e2111400119; https://doi.org/10.1073/pnas.2111400119
“Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein, we provide evidence that SARS-CoV-2 spreads through cell–cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than is SARS-CoV spike, which reflects, in part, their differential cell–cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While angiotensin-converting enzyme 2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the authentic variants of concern (VOCs) B.1.1.7 (alpha) and B.1.351 (beta) have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccinee sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis.”
A personal note:
Last weekend, I met with Mr. Ernest Ramerez, who lost his son to the Pfizer vaccine earlier in the year (verified by a pathologist and a world renowned cardiologist). Mr. Ramirez is determined to not let the death of his only child, Ernesto Ramirez Jr. (Junior) happen to others. Unfortunately, Junior is not the only child to have died by the COVID-19 vaccines.
Whereas, there have been virtually no healthy children die from COVID-19 in the USA. The 700+/- children over the span of two years, who have died of COVID-19, all had significant pre-existing health issues. They died with COVID-19. As I have written many times before, the risk benefit ratio to vaccinating children is upside down.
Mr. Ramirez’ has been censored extensively by big tech and social media. It is difficult to even find a photo of Junior. So to share, this is the life that was taken away from a loving family.
“Face the Nation” had a good segment on how COVID-19 policies are negatively impacting children. It is worth watching.
“They will be paying for our generation’s decisions the rest of their lives”
““They have suffered and sacrificed the most, especially kids in underrepresented, at-risk communities. And now we have the surgeon general saying there’s a mental health crisis among our kids,” Crawford said. “The risk of suicide attempts among girls now up 51% this year. Black kids nearly twice as likely as White kids to die by suicide.”
“I mean school closures, lockdowns, cancellation of sports. You couldn’t even go on a playground in the D.C. area without cops shooing the kids off,” she said. “Tremendous negative impact on kids, and it’s been an afterthought. It’s hurt their dreams, their future, learning loss, risk of abuse, their mental health.”
To Watch, go to:
I hope you will be able to convey this to Mr Ramirez, Dr Malone.
Dear Mr Ramirez - my heart goes out to you and your family. I will be scattering some poppy seeds in my garden which I received from a friend today. I saw them in her garden and they are a beautiful deep burgundy colour. She had promised to save some for me. They will bring great joy to the many bees in my garden, which also make sweet honey for us. Poppies are a symbol of remembrance and I will plant them in remembrance of your beautiful son, Junior. I cannot begin to imagine your loss. I am so deeply sorry.
Thank you for this, Dr Malone. I am going to use that myocarditis study to hammer it home to the university where I work to cease and desist their irrational mandate, for the sake of our students.