Covid-19 News

Many meta-studies include Elgazzar, but most did a sensitivity study removing one at a time.

For example, Bryant used it, and then updated it in a letter - again, showing no major impact in the results.

Neil and Fenton do a Bayesian analysis with sensitivity to Elgazzar

A summary version of this article has been published as a letter in the American Journal of Therapeutics.
https://arxiv.org/ftp/arxiv/papers/2109/2109.13739.pdf

We show that there is strong evidence to support a causal link between ivermectin, Covid-19 severity and mortality, and: i) for severe Covid-19 there is a 90.7% probability the risk ratio favours ivermectin; ii) for mild/moderate Covid-19 there is an 84.1% probability the risk ratio favours ivermectin. Also, from the Bayesian metaanalysis for patients with severe Covid-19, the mean probability of death without ivermectin treatment is 22.9%, whilst with the application of ivermectin treatment it is 11.7%.

Edit : To address concerns expressed about the veracity of some of the studies we evaluate the sensitivity of the conclusions to any single study by removing one study at a time. In the worst case, where (Elgazzar 2020) is removed, the results remain robust, for both severe and mild to moderate Covid-19.

Quote from Fm1

Should I assume they are coming to chop my head off? I'm a member of the local masons lodge and have posted against the mafia, or as I like to say, controlling iinterests. Sometimes you crack me up.

The lower levels are just recruiting and many good people fall into it. Go deeper and see if there is truth here....

Quote from uncertainH

In reviewing that analysis I find a few discrepancies in your statement.

I see

"Version 135 - Removed Naiee"

and

"

Elgazzar.  This study was withdrawn and was removed from this analysis on the same day. There was no significant change (excluding 1 of 66 studies has very little effect, and the exclusion actually improves the treatment delay-response relationship)."

and 44 peer reviewed studies 30 positive RCT

etc etc

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Hi uncertain.

Could you clarify please?

Elgazaar was withdrawn because after an investigation of the data there were bad weirdnesses, RusselSquare withdrew it.

Some problems in the dataset of a large study of Ivermectin for the treatment of Covid-19

This post appears at the same time as this piece at grftr.news  by Jack Lawrence . Jack contacted me to ask if I could help him look at a nu...

steamtraen.blogspot.com

Niaee has been judged high bias by everyone except Bryant et al - which as you know is not exactly an independent meta-analysis. Why did they not judge it high bias? They took an unusual view towards what to include and exclude. We could go into the details.

I'm actually less sure about the problems found in the Niaee data - would be interesting to see them - I think they were the standard weird LS digit distribution thing. This is not 100% reliable. I'd need to check details. What is it you thought was inconsistent about what i said about this?

If you mean that Niaee has also been withdrawn now (after the BBC enquiry and the data they sent) that might be? I'll check if you think it is somehow significant whetehr of not it was withdrawn. From my POV it is the data itself, and other things, that matters, not whether it is actually published.

I've just googled Niaee again and found (I should have paid more attention to it) that it is comparing ivermectin against a placebo arm SOC known from other studies to be more toxic that doing nothing. Which makes it difficult to judge the data anyway. But to be sure how large is that effect and everything else you'd have to do a detailed analysis of the paper. Is it worth that?

Ivermectin now against COVID-19, why…

Ivermectin is the new hydroxychloroquine. But who is its new Raoult? What if the cast of the 2021 sequel will remain otherwise the same?

forbetterscience.com

Quote from Alan Smith

The report states that the president had let the COVID-19 virus kill Brazilians "in a failed bid for herd immunity" and had turned down early vaccines orders, Reuters and the New York Times report. Bolsonaro, who remains unvaccinated and sceptical about the virus, has dismissed the probe, calling it politically motivated.

In fact we should charge all western leaders including Boris, Biden, Merkel, Macron, Dragi,.. for homicide because they ordered the killing of CoV-19 patients by depriving them from working drugs like HCQ, Ivermectin or Nitazoxanide.

In Africa (according Spiegel today) we now have 50..70+% immunity from natural CoV-19 infections. But guess criminals like Gates still want to vaccinate them...

Only fools kill themselves with CoV-19 or a CoV-19 cancer gene therapy (called vaccine)! Have your Ivermectin ready and now during winter season take your daily V-D + zinc!

Quote from Fm1

Should I assume they are coming to chop my head off? I'm a member of the local masons lodge and have posted against the mafia, or as I like to say, controlling iinterests. Sometimes you crack me up.

I can only say that obviously nobody so far did inform your grand master . But I doubt they will force him to spell an order as our forum is just a tiny fig-leave.

Anyway the true music plays in the grand lodge that most members only know by its name (number). And still the grand lodge is not yet the top. Same for rotary where it's called inner wheel the country or region top lodge. On top we have rotary international same for FM.

The greed only members in the FM/R lodges today are typically age 55 or younger. I personally know many of the old guard that have been quite happy with the little favors of tax evasion or job proliferation they got.

In the USA FM/R no longer need tax evasion as their president or congress fellows long time ago already did change the law that did make tax evasion a legal practice. Only the poor (dumb?) working guys with a salary still have to pay taxes...

Today nobody - except some naive people that like the feeling of being elected...- joins FM/R without targeting personal profit.

Quote

president had let the COVID-19 virus kill Brazilians "in a failed bid for herd immunity" and had turned down early vaccines orders

The ultra-liberal ideas of herd immunity share common problem with ultra-vaxxers piling up vaccine boosters in simple fact, that coronavirus mutates and new strains bypass existing immunity: both natural, both gained with inoculation.

Combination Therapy For COVID-19 Based on Ivermectin in an Australian Population

Combination Therapy For COVID-19 Based on Ivermectin in an Australian Population

Note that views expressed in this opinion article are the writer’s personal views and not necessarily those of TrialSite. by Dr. Thomas Borody Background

trialsitenews.com

Note that views expressed in this opinion article are the writer’s personal views and not necessarily those of TrialSite.

by Dr. Thomas Borody

Background

The immediacy of “real-world” data in the pre-hospital treatment of Covid-19 using re-purposed drugs has been the keystone to the development of effective therapy in a pandemic situation. The sense of a “common-message database” for the therapeutic use of ivermectin (IVM) collated by clinicians over a time frame of little more than 12 months, involving patients and research workers across geographic and social lines, is extraordinary. From over 20 countries there are 63 controlled studies accepted for meta-analysis, that have included 47,500 subjects with 625 authors.

While this compelling database on the effectiveness of IVM would not be possible without “real-life” studies, at an individual level, these trials give additional value such as information on dosage and combination therapies. They also give confidence to local doctors and regulators as they seek optimal management strategies.

Here, we report successful pre-hospital treatment of Covid-19 patients in Sydney and Melbourne, Australia, using an ivermectin-doxycycline-zinc combination with an important set of observations on symptom resolution and oximetry.

The Study

Six hundred Australian residents with positive PCR symptomatic Covid-19 were treated with a combination of ivermectin (24 mg per day), doxycycline (100 mg bd), and zinc (50mg per day), for 10 days within 48 hrs of obtaining a positive PCR test for Covid-19. The treatment period was from June to September 2021. Seven percent (7%) were given additional vitamins and nutritional supplements. Only 7% identified adverse events from the therapy, mainly minor gut symptoms of nausea, diarrhoea and heartburn. No patient stopped therapy due to adverse drug events.

A subgroup in hotel and home quarantine was available for a more detailed assessment of symptoms and oxygenation status. This cohort of 126 was assessed for 10 symptoms according to a visual analogue scale (ranging from “0” for no symptoms, to “10” for most severe symptoms). Descriptive statistics are summarised in Table 1. P-Values were calculated using Wilcoxon matched-pairs signed-rank t-tests. Chi Squared analysis was used to analyse rates of hospitalisation in the 600-patient cohort.

The Outcome

A total of 600 patients with positive PCR tests were treated with the ten-day course of “Ivermectin Triple Therapy” (ITT), which was fully completed in over 90% of those treated. None discontinued therapy as a result of drug side effects. Two visited the hospital for less than 24 hours following a transient arrhythmia and then went home, while five were admitted to hospital (0.83%). There were no deaths. In an equivalent control group of 600, not treated with triple therapy, 70 were admitted to hospital (11.5%), with 6 deaths (1%). Chi-squared analysis of hospitalisation rate shows a significant decrease (P<0.001) in the presence of ivermectin triple therapy intervention. The control data was from contemporary infected subjects in Australia obtained from published Covid Tracking Data.

The subgroup of 126 in quarantine had more detailed documentation. They had an average age of 42 (range: 17-94). The results of symptom analysis are in Table 1. For the 10 symptoms analysed, 98% had a total symptom score severity reduction by the end of the treatment period (P< 0.0001). Symptoms that were most persistent were loss of taste and smell, cough, and fatigue. Oximetry readings in 71 subjects were consistent with mild disease in most (Table 1), though the range extended to the low 70’s indicating severe disease in some individuals. At the completion of the 10 -day treatment programme, all subjects had normal oximetry readings.

Comment

This successful study of 600 consecutive subjects treated within 2 days of testing positive on PCR for Covid-19 infection, emphasises the value of early treatment. The results are consistent with the study by Hazan et al, further supporting the value of ITT therapy (ivermectin, doxycycline and zinc).1 The current study differs from that of Hazan et al who successfully used lower doses of IVM and a shorter treatment duration. The current study also confirms the value of oximetry in monitoring response to therapy, with all hypoxic patients having normal oximetry levels following the treatment protocol. Few become hypoxic in the first 48 hours of symptoms. The rapid increase in oximetry values following IVM, noted by Hazan1, confirms significant hypoxia was likely avoided in this treated group. Combining oximetry with visual analogue scales to monitor symptoms, is suggested as a valuable tool for future studies.

Visual analogue scale monitoring of symptoms of Covid-19 infection showed a fall from a median total symptom severity score of 37 (range: 0-100) at the onset of treatment to 3 (range: 0-62) at the conclusion of treatment (P<0.0001). The main persistent symptoms were loss of smell/taste, cough and fatigue, recognised to persist for longer periods, however, all displayed significant severity score reductions during the treatment period (P<0.0001). The impact of early treatment with ITT on subsequent “long Covid” will be an important question to pursue. Symptom resolution with untreated Covid-19 is generally 2-4 weeks, emphasising the value of visual analogue scale assessment.

The major differences in admission to hospital and death following ITT therapy compared to contemporary controls is consistent with the large and increasing body of data measuring the impact of ivermectin-combination therapy.1–3 The results from this study invites comparison with recently announced data by Merck from a study of their re-cycled antiviral polymerase inhibitor, Molnupiravir. The Merck study with 385 treated patients involved a similar group to that treated in the current Australian study judged by near-identical hospital admission and mortality rates in both control groups. In the Merck study, the hospital admission rate was halved (7.3% of treated patients) with no deaths, similar to data for the “first cousin” of Molnupiravir, Favipiravir, which is used extensively in Russia. The important point is that the admission rate in the Merck study is 8-fold greater than the 90% reduction in hospital admissions recorded in the current ITT study (P<0.0001). The public health impact of these findings with a cheap, safe and available therapy, in terms of reduction of load on a health system that will be further stressed as country borders are re-opened, cannot be ignored.

The current study included “real-life” data on consecutive patients thus avoiding selection bias. Therapy was given in two states of Australia, involving over 30 front-line doctors. This compelling data reinforces the value of information from a range of sources and trial methodologies in assessing treatment options, especially in a pandemic situation. The number of patients in this report was capped at 600, as the Australian regulatory body (the TGA) intervened in the middle of Australia’s third Covid wave, to prohibit further prescription of ivermectin for Covid-19 by General Practitioners.

Table 1: Pre and Post Treatment Symptom Severity and Pulse Oximetry Data from Quarantined Individuals (N=126)

Symptom Pre-Treatment Post-Treatment P-Value*

N Mean (SD) Median (Range) N Mean (SD) Median (Range)

Fever 114 4.2 (4.1) 3 (0-10) 114 0.1 (0.7) 0 (0-5) <0.0001

Headache 116 5.8 (3.3) 6 (0-10) 116 0.5 (1.1) 0 (0-5) <0.0001

Cough 120 5.2 (3.3) 5 (0-10) 120 1.1 (1.9) 0 (0-9) <0.0001

Loss of Taste 111 4.1 (4.5) 2 (0-10) 111 1.8 (3.2) 0 (0-10) <0.0001

Loss of Smell 112 4.4 (4.5) 2.5 (0-10) 112 2.0 (3.5) 0 (0-10) <0.0001

Diarrhoea 115 2.3 (3.3) 0 (0-10) 115 0.2 (0.7) 0 (0-5) <0.0001

Vomiting 114 1.0 (2.7) 0 (0-10) 114 0.03 (0.3) 0 (0-3) <0.0001

Fatigue 118 6.6 (3.4) 8 (0-10) 118 1.4 (2.0) 0 (0-10) <0.0001

Muscle Pains 118 5.4 (3.7) 5 (0-10) 118 0.6 (1.4) 0 (0-7) <0.0001

Joint Pains 114 4.7 (3.9) 5 (0-10) 114 0.4 (1.2) 0 (0-7) <0.0001

Total Symptom Severity 124 40.9 (26.1) 37 (0-100) 124 7.5 (10.3) 3 (0-62) <0.0001

Oximetry Reading (%) 71 93.3 (5.0) 95 (71-99) 71 98.1 (1.1) 98 (95-100) <0.0001

Symptoms were scored on a 0-10 scale with 0 being the absence of associated symptom and 10 being the most severe presentation as reported by the patient. Total Symptom Severity Score was a combined sum of all symptoms assessed and was scored out of 100. Oximetry Readings were scored out of 100%. N = the number of respondents and SD = Standard Deviation. *Non-parametric paired t-tests were performed.

Conclusion

In ‘Real Life’ this 10-day Ivermectin Triple Therapy reported here, appears to be a very safe, effective and inexpensive early antiviral treatment for Covid-19. Further detail from the more than 30 doctors involved in treating this patient group, will be used for a formal peer-reviewed publication.

References

1. Sabine Hazan, Sonya Dave, Anoja W. Gunaratne, Sibasish Dolai, Robert L Clancy, Peter A. McCullough TJB. Effectiveness of Ivermectin-Based Multidrug Therapy in Severe Hypoxic Ambulatory COVID-19 Patients. medRxiv. 2021. doi:https://doi.org/10.1101/2021.07.06.21259924

2. Bryant A, Lawrie TA, Dowswell T, et al. Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. Am J Ther. 2021;28(4):e434-e460. doi:10.1097/MJT.0000000000001402

3. Kory P, Meduri GU, Varon J, Iglesias J, Marik PE. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. Am J Ther. 2021;28(3):e299-e318. doi:10.1097/MJT.0000000000001377

A global effort to dissect the human genetic basis of resistance to SARS-CoV-2 infection

A global effort to dissect the human genetic basis of resistance to SARS-CoV-2 infection - Nature Immunology

In this Perspective, Spaan and colleagues propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to…

www.nature.com

Abstract

SARS-CoV-2 infections display tremendous interindividual variability, ranging from asymptomatic infections to life-threatening disease. Inborn errors of, and autoantibodies directed against, type I interferons (IFNs) account for about 20% of critical COVID-19 cases among SARS-CoV-2-infected individuals. By contrast, the genetic and immunological determinants of resistance to infection per se remain unknown. Following the discovery that autosomal recessive deficiency in the DARC chemokine receptor confers resistance to Plasmodium vivax, autosomal recessive deficiencies of chemokine receptor 5 (CCR5) and the enzyme FUT2 were shown to underlie resistance to HIV-1 and noroviruses, respectively. Along the same lines, we propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to SARS-CoV-2 infection.

Main

The COVID-19 pandemic has reminded us that infections are unique among diseases in their potential to rapidly cause massive morbidity and mortality worldwide. Throughout history, infectious diseases have imposed strong selection pressures on humans1,2,3. In particular, viral pandemics, including ones caused by coronaviruses, have occurred repeatedly over the last century, and probably throughout human history4,5,6,7. Clinical variability in response to infection, viral or otherwise, can be explained, at least in some individuals, by human genetic factors8. The introduction of SARS-CoV-2 to a naive population, on a global scale, has provided yet another demonstration of the remarkable clinical variability between individuals in the course of infection, ranging from asymptomatic infections to life-threatening disease9,10,11. Our understanding of the pathophysiology of life-threatening COVID-19 has progressed considerably since the disease was first described in December 2019 (refs. 12,13), but we still know very little about the human genetic and immunological basis of inborn resistance to SARS-CoV-2. Mean secondary attack rates for SARS-CoV-2 infections can reach up to 70% in specific households14,15, and a number of families have been reported in which all the members except one of the spouses are infected16, suggesting that some highly exposed individuals may be resistant to infection with this virus. Here, we review examples of genetically determined susceptibility to severe outcomes of two infectious diseases—tuberculosis (TB) and COVID-19—while covering in greater depth the three known cases of inborn resistance to infections. We then consider candidate genes directly relevant to resistance to SARS-CoV-2 infection. Finally, we propose a strategy for recruiting and genetically analyzing individuals who are naturally resistant to infection with the virus. Above all, we advocate for further studies to develop our understanding of the causal mechanisms of inborn resistance to SARS-CoV-2 infection and provide a framework for the use of this knowledge for therapeutic purposes.

Inborn susceptibility to life-threatening infectious diseases

Human evolution has been marked by microorganisms that are sufficiently pathogenic to exert selective pressure on genes crucial for host defense2. One of the deadliest scourges of human health is TB, which has caused an estimated one billion deaths in Europe over the past two millennia17. Paradoxically, less than 10% of humans infected with Mycobacterium tuberculosis develop TB. Since the turn of the twentieth century, the contribution of human genetics to TB pathogenesis has been deciphered through classic genetics and experimental studies18,19. More recently, rare inborn errors of immunity (IEIs), including autosomal recessive interleukin-12 receptor β1 (IL12RB1)20,21 and tyrosine kinase 2 (TYK2) deficiencies22, in particular, have been identified in a few people with TB. The broader relevance of this finding was shown when the analysis was expanded to more common variants, revealing that homozygosity for the TYK2(P1104A) polymorphism was associated with a high risk of developing TB17,23. p.P1104A homozygosity disrupts the capacity of TYK2 to mediate IL-23-dependent IFN-γ immunity to mycobacteria23. Its minor allele frequency is highest among Europeans17. An analysis of ancient DNA showed that the frequency of TYK2(P1104A) has strongly decreased over the last 2,000 years in Europe owing to strong negative selection, concomitant with the high TB burden in Europe24.

With the advent of the COVID-19 pandemic, specific IEIs were shown to have a role in defining susceptibility to severe COVID-19. The COVID Human Genetic Effort (http://www.covidhge.com) reported 23 critically ill people with IEIs at 8 loci governing TLR3- and IRF7-dependent type I IFN induction and amplification13. Remarkably, four unrelated and previously healthy adults had autosomal recessive IRF7 or IFNAR1 deficiency. Although rare, the individuals with IEIs demonstrate that type I IFN immunity is indispensable for the control of SARS-CoV-2 infection. This finding led to the subsequent discovery, also by the consortium, of pre-existing neutralizing autoantibodies against type I IFNs as a phenocopy of type I IFN-related IEIs12. Subsequent studies in independent cohorts confirmed the presence of neutralizing autoantibodies against type I IFNs in more than 10% of people with severe COVID-19 (refs. 25,26,27,28,29,30). More recently, the consortium found that autoantibodies neutralizing lower, more physiological concentrations of type I IFNs account for about 20% of patients older than 70 years with critical pneumonia31. Moreover, the consortium also reported that about 1% of male patients younger than 60 years of age with critical pneumonia have X-recessive TLR7 deficiency32. Surprisingly, the individuals with IEIs identified and those with autoantibodies had not displayed any particular susceptibility to other severe infectious diseases before exposure to SARS-CoV-2. This finding is consistent with the smaller amounts of type I IFNs induced by SARS-CoV-2 than by seasonal influenza virus, for example33. However, type I IFN autoantibodies have been shown to underlie a third of adverse reactions to the live attenuated yellow fever virus vaccine34. Collectively, these examples illustrate how the genetic elucidation of an immunological deficit in a few rare individuals can indicate a mechanism that is disrupted by other causes in many more people.

Inborn resistance to infection upon exposure

An individual’s genetically determined protection against an infectious disease is the mirror image of genetically determined susceptibility to life-threatening disease. The term ‘protective’ is applied to a given locus when the allele associated with a lower risk of disease is the least frequent, alternative allele. Far fewer genetic studies on infectious diseases have focused on protective alleles than on susceptibility to infection, whether monogenic or polygenic. In the early 1950s, Anthony Allison showed that the HbS sickle-cell trait is maintained at high frequency in African areas where malaria is endemic, owing to a heterozygous advantage1 of the allele for providing protection against severe Plasmodium falciparum infections35. Other examples of protection against poor infection outcomes include the occurrence of specific HLA class I alleles in long-term nonprogressing HIV-1-infected individuals36, and the role of a type III interferon (IFNL3-IFNL4) haplotype in viral clearance following infection with hepatitis C virus (HCV)37,38. These alleles confer protection against severe disease in infected people, but not against contraction of the infection itself.

The genetic determinism of resistance to infection has been even less studied than that of protection against poor infection outcomes, and study has always been from a monogenic angle. Only three mechanisms of Mendelian resistance to infection have been identified to date. In the 1970s, Louis Miller discovered that the absence of the Duffy antigen on erythrocytes prevented these cells from becoming infected with Plasmodium vivax39,40. The molecular genetic basis of this autosomal recessive resistance trait was not determined until the 1990s. The causal variant affects the GATA-1 binding site in the DARC promoter, selectively preventing gene transcription in erythroid cells41. At about the same time, autosomal recessive CCR5 deficiency was found to confer resistance to infection with HIV-1 (refs. 42,43,44). The most common loss-of-function mutation in CCR5 is a 32-base-pair deletion with a minor allele frequency of 10% in the European population. Finally, autosomal recessive FUT2 deficiency was discovered to confer resistance to gastrointestinal infections with noroviruses45. As for DARC and the P. vivax Duffy binding protein, and CCR5 and the HIV-1 gp120–gp41 heterodimer, FUT2 expression is required for binding of the norovirus VPg capsid. It is probably no coincidence that these examples of Mendelian resistance to infection are complete deficiencies of receptors or coreceptors exploited by the pathogen as a means of entering cells. The genetic mechanisms of protection against severe infectious outcomes and those underlying resistance to infection itself are both subject to positive selection, as they provide a survival advantage46.

Candidate SARS-CoV-2 resistance genes

The proportion of humans naturally resistant to SARS-CoV-2 infection is unknown, but a number of candidate genes potentially involved in human inborn resistance to SARS-CoV-2 infection have emerged from several lines of evidence. One is the ABO locus, which was identified in genome-wide association studies (GWAS)47,48. Although initial data on the impact of blood group on COVID-19 severity were inconsistent, a recent meta-analysis of nearly 50,000 people from 46 studies confirmed an effect of this locus on susceptibility to infection49. The protective effect of the O allele, however, is small, with an odds ratio of ~0.90. Although no unified mechanism of resistance has yet been proposed50, ABO blood groups may play a direct role in infection by serving as coreceptors for SARS-CoV-2 (ref. 47). Pandemic-associated pernio (chilblain) is a rare manifestation in individuals exposed to SARS-CoV-2 that could provide insight into mechanisms of resistance to infection51,52. Pandemic-associated pernio (‘COVID toes’) mimics the skin lesions of familial chilblain lupus and Aicardi–Goutières syndrome, monogenic disorders caused by mutations leading to an upregulation of type I IFN signaling53. Most people with pernio remain seronegative, but the presence of the SARS-CoV-2 spike protein has been demonstrated in skin biopsy specimens, and a robust local type I IFN response has also been observed, suggesting early clearance of the virus54. These observations imply the presence of infection, and, thus, the absence of natural resistance to infection. Nevertheless, by understanding the pathophysiology of this phenomenon, we may be able to shed light on host mechanisms restricting viral replication and promoting resilience upon SARS-CoV-2 infection.

In vitro interactome studies have identified additional candidate host genes supporting the viral life cycle. Early in the pandemic, it was discovered that SARS-CoV-2 infection is dependent on the ACE2 receptor for cell entry and the serine protease TMPRSS2 for spike protein priming55,56,57,58. Indeed, a rare variant located close to ACE2 was found, by GWAS, to confer protection against SARS-CoV-2 infection, possibly by decreasing ACE2 expression59. Furthermore, although their impact on infection is unknown, some human ACE2 polymorphisms bind the SARS-CoV-2 spike protein with different affinities in vitro60. In a genome-wide CRISPR knockout screen for infection with SARS-CoV-2 and other coronaviruses, TMEM41B was identified as a requirement for permissive infection with the virus61. TMEM41B is an endoplasmic reticulum transmembrane protein that is also required by flaviviruses62. Its impact on SARS-CoV-2 infection remains to be established, but an allele common in East and South Asians has been shown to be associated with a lower capacity to support flavivirus infection in vitro62. Like genome-wide CRISPR knockout screens, affinity purification-mass spectrometry on human proteins interacting with SARS-CoV-2 has yielded an extensive protein interaction map63,64. Functional assessments of this interactome have resulted in its translation into a catalog of essential host factors required for SARS-CoV-2 infection65. Although no human studies linking the SARS-CoV-2 interactome to susceptibility to infection have yet been published, the genes concerned—along with the loci identified by GWAS—can be regarded as candidates for the identification of inborn variants conferring resistance to infection.

Genetic and immunological strategies

There are two key challenges in the search for individuals naturally resistant to SARS-CoV-2 infection. First, demonstrating an absence of infection poses a diagnostic hurdle. PCR-based molecular diagnostic approaches using respiratory specimens provide only snapshot information. Serology is useful for assessing the occurrence of prior infections for many viral infections, but some individuals remain seronegative despite infection with SARS-CoV-2 (refs. 66,67). Pre-existing crossreactive T-cell-mediated immunity as a result of prior infections with other coronaviruses might contribute to a resilient response upon infection with SARS-CoV-2 (refs. 68,69,70,71). At the same time, T cell responses to SARS-CoV-2-specific antigens could provide a sensitive and specific marker for the qualitative assessment of prior infection with SARS-CoV-2 (ref. 68). A second challenge lies in the probability of virus transmission. The likelihood of infection is influenced by both the duration and intensity of exposure to an infected individual, and the intrinsic transmission characteristics of the pathogen. The basic reproduction number (R0, the average number of secondary infections produced by a typical case of an infection in a population where everyone is susceptible) of SARS-CoV-2 is between 2.5 and 5.0, on average72,73,74. However, coronaviruses are known to be transmitted during superspreader events with very high secondary attack rates75. Identifying these events, other large-scale outbreaks, and households in which one or very few individuals remained uninfected14,15,16 would be of particular interest for the study of inborn variants conferring resistance to SARS-CoV-2.

When testing the hypothesis that monogenic inborn variants of immunity confer natural resistance to SARS-CoV-2 infection, we apply a four-step strategy to overcome diagnostic limitations and uncertainties about exposure (Fig. 1). We first focus on uninfected household contacts of people with symptomatic COVID-19 (score of 3 or higher on the World Health Organization’s clinical progression scale76). We then consider individuals exposed to an index case without personal protection equipment, for at least 1 hour per day, and during the first 3–5 days of symptoms in the index case. Priority is given to the study of serodiscordant spouses and sleeping partners. We subsequently enroll individuals with a negative PCR result when tested plus negative serological results obtained 4 weeks after exposure. Finally, we assess SARS-CoV-2-specific T cell responses in the candidate resistant individuals and compare their responses with those of SARS-CoV-2-infected individuals. We differentiate T cell responses induced by vaccination from those provoked by natural infection. Study participants lacking a SARS-CoV-2-reactive T cell response will be analyzed by whole-exome/genome sequencing. The results will be compared with those for SARS-CoV-2-infected controls, with the aim of identifying rare or common variants with a strong effect on resistance to infection11,12,13,77. Finally, as in studies of IEIs78, the genetic findings will be validated experimentally, including with cells from the study participants, to dissect the mechanisms of resistance at the molecular, cellular, tissue, immunological, and whole-organism levels (Fig. 1).

Fig. 1: A global effort to dissect the human genetic basis of resistance to SARS-CoV-2 infection.

figure1

Inclusion criteria, and approach for the identification and validation of inborn variants conferring resistance to SARS-CoV-2 infection (http://www.covidhge.com). Created with BioRender.com.

Full size image

Concluding remarks

Historical examples of inborn resistance to infection with other pathogens provide a road map for testing the hypothesis of monogenic inborn resistance to infection with SARS-CoV-2. Some more common inborn variants of resistance in candidate genes may have relatively small effects. However, we also aim to identify candidate genes with potentially rare variants and a large effect size. These variants are of particular interest for two reasons. First, they can provide a deep understanding of the essential biological pathways involved in infection with SARS-CoV-2. Second, they will allow for the development of innovative therapeutic interventions to prevent or treat SARS-CoV-2 infection in others. The proof-of-principle for this second reason of interest has been provided by CCR5 and its antagonist maraviroc, which is used for the treatment of HIV-1 infections in specific settings79. In addition, transplantation of CCR5-deficient bone marrow has been successfully applied to cure HIV infection in a few people80,81. No specific drug effective against COVID-19 has been discovered since the start of the pandemic. Lessons learned from experiments of nature could potentially guide us toward such specific treatments for COVID-19. We have already enrolled more than 400 individuals meeting the criteria for inclusion in a dedicated resistance study cohort. The collaborative enrollment of study participants is continuing (http://www.covidhge.com), and subjects from all over the world are welcome

Quote from Wyttenbach

I can only say that obviously nobody so far did inform your grand master . But I doubt they will force him to spell an order as our forum is just a tiny fig-leave.

Anyway the true music plays in the grand lodge that most members only know by its name (number). And still the grand lodge is not yet the top. Same for rotary where it's called inner wheel the country or region top lodge. On top we have rotary international same for FM.

The greed only members in the FM/R lodges today are typically age 55 or younger. I personally know many of the old guard that have been quite happy with the little favors of tax evasion or job proliferation they got.

In the USA FM/R no longer need tax evasion as their president or congress fellows long time ago already did change the law that did make tax evasion a legal practice. Only the poor (dumb?) working guys with a salary still have to pay taxes...

Today nobody - except some naive people that like the feeling of being elected...- joins FM/R without targeting personal profit.

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My post was in jest but you are right, most members are highly involved in community rotary. It's also a great way for networking. My interest for joining was free fishing trips, a lodge on the lake and 24/7 access. Members of my lodge raised over 10 grand, mostly stimulus money and bought cases of vitamin d and passed them out to assisted living facilities in central Florida and we plan to raise 20 grand by end of year to do it again.

Quote from THHuxleynew

Could you clarify please?

I'm simply looking at the information supplied here:

They have details of revisions, exclusions, links to papers as well as links to other studies or other drugs

Ivermectin for COVID-19: real-time meta analysis of 63 studies

Ivermectin for COVID-19. Early treatment - 72% improvement, p < 0.0001. All studies - 68% improvement, p < 0.0001. 1 in 1 trillion probability results of the…

ivmmeta.com

Quote from Zephir_AWT

ultra-liberal ideas of herd immunity

Fascinating sociological analysis of what I thought was basic epidemiology.

Quote from uncertainH

I'm simply looking at the information supplied here:

They have details of revisions, exclusions, links to papers as well as links to other studies or other drugs

https://ivmmeta.com/

I understand that - they are not entirely accurate, being a pro-ivermectin PR site. Still, I'm not aware of gross errors in that list. Where is it inconistent with what i've said?

Quote from THHuxleynew

Where is it inconistent with what i've said?

Simple. You said:

Quote from THHuxleynew

The RCTs are negative

The link provided does not support this statement. The vast majority look positive.

You said:

Quote from THHuxleynew

one (Elgazaar) of which had so many obvious issues with its raw data it is generally considered to be fraudulent and was withdrawn. The other (Niaee) also eventually coughed up data after pressure, and the data was also found to be inconsistent.

Agreed but these are removed from this meta analysis.

and now you've said:

Quote from THHuxleynew

they are not entirely accurate, being a pro-ivermectin PR site

"Not entirely accurate" is a blanket statement you should really be specific. Which of the 66 studies are not entirely accurate and why. Or are there issues with the methodology of the meta analysis and why.

"Being a pro ivermectin PR site" is a dismissive statement based on opinion and emotion. PR for whom? Just as anti-vaxxers should not dismiss everything coming from a pharma company as pro-vax PR nor should you do the opposite. Apply the same burden of proof to things you believe in as things that you don't. If there are problems with the analysis I would sincerely like to know what they are.

Quote from Fm1

A total of 600 patients with positive PCR tests were treated with the ten-day course of “Ivermectin Triple Therapy” (ITT), which was fully completed in over 90% of those treated. None discontinued therapy as a result of drug side effects. Two visited the hospital for less than 24 hours following a transient arrhythmia and then went home, while five were admitted to hospital (0.83%). There were no deaths.

This fully explains what we know from Uttar Pradesh. Ziverdo kit gives you 100% protection for CoV-19

Quote from Fm1

In an equivalent control group of 600, not treated with triple therapy, 70 were admitted to hospital (11.5%), with 6 deaths (1%).

This is sad clowns news. 70:2 hospital visits - but quite common for placebos in other IVR studies too.

I do not discuss about the 6 deaths I already complained about this 2020 with the Elgazzar study. No treatment is killing people. But in FM/R countries this is standard care.

Israel update:: https://datadashboard.health.gov.il/COVID-19/general

It took at least 2 weeks to get the real age 60+ booster deaths number that are now far higher than communicated. The death among 2,3 x vaccinated are just a tick lower than for unvaccinated. But worst:: The booster makes no difference at all.

So vaccines still do protect quite a bit but compared to early ziverdo treatment they are a killer!

Although IVMeta is associated (affiliated?) with pro-IVM FLACC etc, haven't found any major errors in their data or their methodology.

They are very open about what studies they include or exclude, and why. They excluded Elgazzar "same day", and others when the authors informed them of upcoming retractions.

New CDC report format (ongoing, currently from 16 jurisdictions - states or big cities)

Rates of COVID-19 Cases and Deaths by Vaccination Status

<https://covid.cdc.gov/covid-da…/#rates-by-vaccine-status>

April to Sep 4 (One month behind to allow for correct coding)

Overall : Unvaxed 6.1 * chance of positive test 11.3 * chance of death

By vaccine : All better than unvaxed, but Moderna the best

By age: Very curious : 12-17 unvaxed has double the case rate of 80+ unvaxed.

Quote from uncertainH

The link provided does not support this statement. The vast majority look positive.

So: you need to select the RCTs which are of high enough quality to be useful in a meta-analysis. Bryant et al, the most pro-ivermetcin (run by FLCC and BIRD as the two lead authors are in them, hardly unbiased), selects (16?0 of the RCTs as OK. When Niaee and Elgazzar are removed from this the result is negative.

Quote from uncertainH

Agreed but these are removed from this meta analysis.

and now you've said:

The ivermeta list is not a meta-analysis - no way. Please read any of the available publishedmeta-analyses to see what they do and why. In spite of being biassed in its selection of RCTs pro-ivermectin - it includes (and refused to remove) Elgazzar now withdrawn - Bryant would be a possible place for you to start. secure in the knowledge that the authors are highly motivated to be pro-ivermectin. Tables 4,5,6 are useful showing whta happens as you rgo from all studies to those demed by this pro-ivermectin study to be at low risk of bias. There is a standard cochrane methodology for this. Oh, and google Cochrame ivermectin meta-analysis for the Cochrame group (very objective) view of ivermetin evidence. it is negative, like their view of remdesivir evidence.

Quote from uncertainH

"Not entirely accurate" is a blanket statement you should really be specific. Which of the 66 studies are not entirely accurate and why.

You will note in my posts here i usually provide more details than most. In this case I was referring to the list, not the studies. I remember vaguely the list had some issues, but not what they were and no time to find them. the studies - well others have found a number fraudulent, and objective meta-analyses reckon most of them are at very high risk of bias - the observational ones for obvious reasons. Read the published meta-analyses (several - all different) for an idea of methodology. there is also an interesting paper looking specifically at the issue of bias, from somone who is generally interested in this:

In addition, here is some context:

chemistryworld.com/news/ivermectin-debacle-exposes-flaws-in-meta-analysis-methodology/4014477.article

This is hilarious:

This is too: