Coronavirus Update 69 plus other stuff

Omicron US strains: as of August 13th data - variants make up: BA.4 is 3.6%, BA.4.6 is 7.5% and BA.5 is 88.7%. This Covid wave is still inline with volumes from wave three which was delta.

BA 4.6 and BA.4 are still not fairing well against BA.5.

BA.5 is showing no signs of increased disease morbidity.

R0 infectiousness is in the range north of measles: the new reproductive rate is 1 infects 12 which infects 144 which infects 1,728 which infects 20,736 which infects 248,832. That is a very very fast spread rate and likely an underestimate.

Little else to report here. (CDC Variants)

Quick Hits and other musings -

1) In the interview with Dr. Offit there were a few big take aways:

·     Boosters for non risk based teen and young adults are unlikely to provide benefit while offering a small but real level of risk from myocarditis

·     Boosters are offering minimal benefit to the nation from a transmission perspective. At best 8-12 weeks of protection against symptomatic disease

·     Dr. Offit voted against adding omicron antigens to this fall's booster as there was limited data that it would any benefit. He was in the minority at the FDA advisory meeting, thus this fall's booster will have new strain genetics in it

·     The boosters could, not shown yet in humans, block future variant immunity to newer strains through viral immune imprinting

·     Humans need to pay more attention to their health to mitigate disease over time

·     We, as a society, need to stop tiptoeing around the concepts of lifestyle induced disease risk and in a non judging manner educate everyone in the risk categories, i.e

·     He clearly stated that we have achieved our goal with vaccinations, the reduction of death and hospitalization and it appears the 2 dose primary series was enough to achieve it

·     High risk groups are the ones that should vaccinate every time a new one is available based on the guidelines

In a recent piece in Time Magazine, Dr. Offit also offered the following: "That has vaccine experts divided. Dr. Paul Offit, a member of the advisory committee, says this strategy makes him “uncomfortable” for several reasons. He notes that the data presented from Pfizer-BioNTech and Moderna in June involving their BA.1 booster shot, which focused on the levels of virus-fighting antibodies the vaccine generated, were underwhelming. “They showed that the neutralizing antibody titers were between 1.5- and two-fold greater against Omicron than levels induced by a booster of the ancestral vaccine,” he says. “I’d like to see clear evidence of dramatic increase in neutralizing antibodies, more dramatic than what we saw against BA.1, before launching a new product. We’re owed at least that.” While conducting human studies does take more time, Offit says even a small trial involving about 100 people to measure their antibody levels after getting a BA.4/5 booster would be helpful. “You can boost people and measure their neutralizing antibodies two weeks later,” he says. Such information could also be critical in setting realistic expectations for the Omicron booster. The public might feel it’s a panacea that signals the end of the pandemic, but without any data showing how well the booster will protect people from not only getting sick, there might be unrealistic expectations about what the boost can do. “I get a little nervous, frankly, when I hear this [booster] is going to be miraculous,” Offit says."

For the Counter argument in the Time Piece: “The totality of evidence is relevant here,” says Dr. Ofer Levy, director of the precision vaccines program at Boston Children’s Hospital, and also a member of the FDA’s vaccine advisory committee. “We are in a situation where we need to pivot as variants emerge, and if we try to be too rigid in our approach, we will always be behind, and not giving the population optimal protection.”

Levy says that the latest Omicron-specific boosters that the FDA is considering contain a combination of mRNA targets against both the original virus and Omicron BA.4/BA.5, so the data on safety and efficacy from the original vaccine in protecting against hospitalization and death is relevant. While the data on this vaccine does come from animals, using that data to decide whether or not to authorize the booster is a matter of “hedging bets.” There is data showing that even vaccinated and boosted people can get mild to moderate COVID-19 disease, because their vaccine-induced protection is waning, so boosting with a shot that is better matched to the Omicron subvariants circulating now is a reasonable bet, even if the data on its efficacy comes from animals and not people. “I think it’s the right decision,” says Levy. (Park A. 2022)

I stand in the same camp as Dr. Offit. I am not into hedging bets when my risk of death sits at 0.000033 currently. Death rate from Covid sits at its lowest level to date in the is pandemic/endemic reality. I remain grateful that people like Dr. Offit are looking at the data in the context of risk and not just blanket guidelines which are not individualized or at least by risk stratification.

2) From JAMA we find that 88% of patients reporting a smell or taste dysfunction after contracting Sars2 completely recovered within 2 years. 11% of patients took up to 2 years to recover whereas most recovered by 6 months post illness. This was a small study and pre omicron. The key piece is that it appears that most if not all are fully recovering despite the other studies that showed brain mass loss in the olfactory regions which initially portended bad and long term concerns. (Boscolo-Rizzo et. al. 2022)

3) If you are interested in the intermediary animals that could play a role in future shifts to Sars2 genomics, this article discusses possible intermediary animals for future risk. (Madhusoodanan J. 2022)

4) "SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID1–3. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions1–3; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID. Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus. Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID." (Klein et. al. 2022)

This is a very important study as it leaves us with some biomarkers of disease etiology with elevated antibodies against EBV, which is infectious mononucleosis, as well as lower cortisol hormone levels. We have noted the elevated EBV levels in our clinic in chronic fatigue teenagers and PACS patients. These results reflect a burnt out immune stress hormonal axis. SARS2 is known to dramatically alter immune activity in the very ill with exhausted T cells noted in those that recover post hospitalization. Exhausted T cells have limited capacity to handle viral illnesses. Thus, latent herpesviridae like EBV and CMV could pose a further stressor on the system further utilizing resources to try to handle these infections that were previously dormant. This is tiring. In my mind, this is further evidence that long Covid is a genetic immune viral mismatch. (Amhadi et. al. 2022)

I think that we are seeing repeated pictures of human immune dysregulation that drives the inability of the immune system to handle effectively viral and/or bacterial pathogens leading to chronic immune activation leading to exhaustion and diseases like CFS (Chronic Fatigue Syndrome) PANDAS (pediatric autoimmune neuropsychiatric disease associated with streptococcus) or PANS from other pathogens.

The reality appears to be that with different variables in play including gastrointestinal dysbiosis, immune exhaustion, auto antibodies against viral killing mechanisms and hyper inflammation and host genetics driving long term disease. See the next paper.

5) "The kinetic aspects of this longitudinal investigation were revealed in a number of ways. First, GI PASC uniquely correlates with the newly expanded cytotoxic CD8+and CD4+T cell populations at T3, including SARS-CoV-2-specific clonotypes, which get activated not during acute disease but at convalescence when PASC was identified. Whether this correlates with the reported GI viral shedding that can occur in some post-acute COVID-19 patients will require additional studies, but the finding that GI PASC also involves bystander activation of CMV-specific T cells suggests that additional levels of non-specific T cell activation may also contribute to GI PASC. The activation of auto-reactive T cells has been reported in many infection settings, including COVID-19." (Su et. al. 2022)

Yonkers et. al. found similar findings in children with MIS-c making the gut potential ground zero for PASC and probably also Chronic fatigue as time will elucidate. (Yonkers et. al. 2021)

I keep honing in on this data for these reasons: a) we are stuck with SARS2 and other viral pathogens b) repairing your gut microbiome may prevent MIS and PACS post infection c) stress, sleep and exercise are a piece of this puzzle c) immune health keeps leading us back to our diet and immune responses

6) Risk of myocarditis is much higher following infection than vaccination says a new study in the Journal Circulation. However, when broken down by subgrouping, "Associations were stronger in men younger than 40 years for all vaccines. In men younger than 40 years old, the number of excess myocarditis events per million people was higher after a second dose of mRNA-1273 than after a positive SARS-CoV-2 test (6 fold higher). In women younger than 40 years, the number of excess events per million was similar after a second dose of mRNA-1273 and a positive test." (Patone et. al. 2022)

We are finally doing what we should have done a long time ago. Stratifying by age, risk, co morbidity, etc... In the age of machine learning, it is inappropriate that we are giving blanket statements like, "everyone over 12 years of age should receive a booster Covid vaccine".

7) From the NEJM: Design: A phase 3, randomized, controlled trial tested metformin, ivermectin, and fluvoxamine in nonhospitalized adults with overweight or obesity who were enrolled within 3 days after the diagnosis of SARS2 infection. 1323 patients received immediate release metformin for 14 days; ivermectin for 3 days; fluvoxamine for 14 days; metformin and ivermectin; metformin and fluvoxamine; or placebo. The primary outcome was a composite of hypoxemia reported by the patients, emergency department visit, hospitalization, or death due to Covid-19. At 14 days, a primary-outcome event had occurred in 26% of participants overall, and the incidence did not differ according to treatment group.(Bramante et. al. 2022)

This is a well done analysis using one of the greatest risks of death as the patient test population, obesity. We are left knowing that these meds are not preventing death.

8) Science Heavy - From Nature Communications we see some potential therapeutic news that is exciting. "Mutational enhancement of SARS-CoV-2 viral fitness can arise from effects on receptor engagement and evasion of neutralizing antibodies, with structural origins in the spike glycoprotein. Here we have examined these effects, demonstrating domain-specific differences in the roles and structural mechanisms of S protein mutations. Although such mutational changes can pose threats to natural and vaccine-induced immunity, the existence of preserved epitopes within functional domains holds great potential for future antigenic focus. This is highlighted in our analysis of variant SARS-CoV-2 spikes, which despite exhibiting effects on antibody evasion and ACE2 binding, shared a conserved epitope within the Receptor Binding Domain which conferred broad neutralization.

The structural impacts of VoC S protein mutations offer insight regarding the differing mutational heterogeneity observed for the N Terminal Domain and RBD. While VoC mutations within the RBD are limited to only substitutions, the NTD hosts a large array of deletions and substitutions, along with one documented insertion as seen in the BA.1 subvariant. These NTD mutations predominantly localize to the three loops constituting the “NTD neutralization supersite”. Our structures of VoC S proteins in complex with ACE2 demonstrate minimal structural changes in the RBD, reflecting its functional constraints in cell attachment, only permitting mutations that preserve the ACE2 binding interface.

In contrast, our structure of the Gamma NTD confirms the role of mutations within this domain as enabling structural rearrangement of antigenic loops, a feature common to all variant spike NTDs (Alpha, Beta, Delta, Epsilon, BA.1, BA.2). These rearrangements are likely directed primarily by immune-evasive pressures. Taken together, these contrasting structural effects between variant NTD and RBD mutations likely arise due to different functional requirements and selective pressures between these domains. Despite these domain-specific mutational pressures, several lines of evidence have emerged from the present study demonstrating the existence of pan-variant epitopes." (Mannar et. al. 2022)

In laymen's terms this basically means that the spike protein of all of the variants of concern appears to have a region on the spike protein that could be a universal target for an antibody to neutralize the ability of SARS2 to do its replicative damage. This could lead to a medicine that works for the at risk individuals of the future.

That's all this week,

Dr. M

Park Time Magazine

Boscolo-Rizzo JAMAEnt

Madhusoodanan JAMA

Klein MedRxIV

Amhadi Int J Endocrinology

Su Cell

Yonkers J Clin Inves

Patone Circulation

Bramante NEJM

Mannar Nature Communications

CDC MMWR

CDC Variants Page

CDC Covid Deaths