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About viruses and viral disease

Trial By Error: Some National Health Service Branches Fail to Respond to New NICE Guidelines for ME/CFS

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By David Tuller, DrPH

In late October, the UK’s National institute for Health and Care Excellence (NICE) released its new ME/CFS guideline, which specifically recommend against graded exercise therapy (GET) and a specialized form of cognitive behavior therapy (CBT). Last week, I wrote about how King’s College London continues to host a page on “CBT and chronic fatigue syndrome,” which boasted that “our researchers were among the architects of bespoke talking therapy for chronic fatigue syndrome, which is now one of two treatments recommended in the UK.” (This page is still live as of this writing.)

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Trial By Error: Is Something Shifting at the Science Media Centre?

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By David Tuller, DrPH

For years, London’s Science Media Centre has fiercely promoted research into graded exercise therapy (GET) and cognitive behavior therapy (CBT) for the illness or cluster of illnesses variously referred to as chronic fatigue syndrome, myalgic encephaloymyelitis, CFS/ME, ME/CFS, and other names. Some of the prominent experts in this field have had close relationships with this specialized public relations agency.

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TWiV 829: Antiviral and cytotoxically empowered for COVID-19

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A TWiV duo reviews how SARS-CoV-2 attacks the olfactory mucosa but spares the olfactory bulb, vaccination with BNT162b2 induces virus-specific stem cell memory T cells, and development of an oral protease inhibitor for the treatment of COVID-19.

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Show notes at microbe.tv/twiv

Red blood cells are immune sentinels

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Did you know that the innate immune DNA sensor TLR9 is on the membrane of red blood cells? I didn’t know that. To learn about why it’s there, listen to Immune episode #50. In that episode we review evidence that toll-like receptor 9 on the surface of red blood cells binds DNA, leading to uptake by macrophages and innate immune activation.

Pills for COVID-19

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Multiple vaccines have been developed that have made substantial contributions to controlling the COVID-19 pandemic, but where are the antivirals? Only repurposed drugs have been used and not with much success. That situation seems about to change with the authorization of drugs that target the RNA polymerase (Molnupiravir) and a viral protease (Paxlovid).

Molnupiravir is an orally available pro-drug of the nucleoside analog N4-hydroxycytidine (NHC). The latter is a nucleoside analogue which is incorporated into RNA by the viral RNA-dependent RNA polymerase. Once incorporated into RNA, NHC is recognized as either C or U by the RNA polymerase. As a consequence, many mutations are introduced into the viral genome, causing lethal mutagenesis and inhibition of infectivity. NHC has been shown to block SARS-CoV-2 transmission in ferrets.

Interim results in 775 patients of a phase 3 clinical trial with molnupiravir show that the drug reduced hospitalization or death about 50% compared with placebo in patients with mild to moderate COVID-19: 7.3% of patients who received molnupiravir were either hospitalized or died through Day 29 (28/385), compared with 14.1% of placebo-treated patients (53/377). No deaths were reported in patients who received molnupiravir, as compared to 8 deaths in patients who received placebo, through day 29. The trial required that all patients have laboratory-confirmed COVID-19 with symptom onset within 5 days of assignment to control or drug group. Patients were recruited from multiple countries and included those with risk factors for poor disease. Merck expects to produce 10 million doses of the drug in 2021 and has submitted an application for emergency use authorization (EUA).

Paxlovid is an inhibitor of the 3CL or main protease of SARS-CoV-2, an essential viral enzyme that is required to process precursor proteins into functional products. The drug works by binding to the active site of the protease. Such inhibitors have been successfully developed and are approved for the treatment of AIDS and hepatitis C. Paxlovid inhibits viral reproduction in cell culture and in virus-infected mice when given orally. In a phase I trial in 4 participants, the drug was safe and well tolerated and reached levels greater than needed to inhibit reproduction in cell culture.

Interim analysis of a phase 2/3 randomized, placebo-controlled study of Paxlovid showed that the drug reduced the risk of hospitalization or death by 89%. This study enrolled non-hospitalized patients with COVID-19 who were at risk for severe illness. The patients were treated with Paxlovid within 3 days of symptom onset. Of the patients who received the drug, 3/389 were hospitalized through day 28 (0.8%) compared with 27/385 in the placebo group hospitalized and 7 deaths (7%). Similar results were obtained in a group of patients treated within 5 days of symptom onset. Based on these results, Pfizer plans to submit an application for EUA.

The only antiviral repurposed for SARS-CoV-2 that had any efficacy is remdesivir, whose widespread adoption is limited by the need to administer the drug intravenously. Because they are taken orally, Molnupiravir and Paxlovid should have a far greater impact on the pandemic, especially for people who refuse to be vaccinated. If these drugs had been available before the pandemic – which was certainly possible – it might have been largely prevented.

Trial By Error: Authors Alicia Butcher Ehrhardt and Nasim Marie Jafry Discuss Their Novels

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By David Tuller, DrPH

It is hard enough to write when you’re feeling healthy. So I’m in awe of people who manage to write despite suffering from a debilitating chronic illness—especially one that messes around with cognitive functioning. That number includes some ME patients who have written novels. (I don’t write fiction; I have a hard enough time keeping up with real life.)

Alicia Butcher Ehrhardt and Nasim Marie Jafry have both accomplished this impressive feat–their novels, respectively, are Pride’s Children PURGATORY and The State of Me (links are to Amazon.com). Both books feature a sympathetic central character who struggles with her illness. The portrayals clearly draw credibility and granularity from the authors’ own intimate engagement with the issue.

I’ve asked these authors to offer some thoughts on their books.

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Trial By Error: King’s College London Is Still Hyping “Bespoke” CBT for CFS as “Recommended” in UK

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By David Tuller, DrPH

A week ago, Britain’s National Institute for Health and Care Excellence published its new, evidence-based guideline for ME/CFS, which recommended against graded exercise therapy and cognitive behavior therapy offered as curative rather than as supportive care. Not surprisingly, this event creates some public relations problems for members of the CBT/GET ideological brigades, who have spent years promoting their dysfunctional beliefs that their favored interventions can cure the illness.

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Spikevax Induces Durable Protection from the Delta Variant in Rhesus Macaques

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by Gertrud U. Rey

It is currently not clear how long SARS-CoV-2 vaccine-induced immunity lasts. The gold standard for determining the efficacy of a vaccine is the “challenge” study, which involves intentionally infecting immunized subjects with the pathogen against which they were immunized. Such studies are typically done in non-human primates, because it is unethical to deliberately infect humans with pathogens that cause serious morbidity and mortality.

A recent preprint by Kizzmekia Corbett and others describes experiments done to assess the efficacy of Moderna’s SARS-CoV-2 “Spikevax” vaccine in rhesus macaques one year after vaccination. The authors immunized eight animals with two doses of Spikevax at four-week intervals and then collected blood samples, nasal swabs, and lung wash samples at various time points over the course of the following year. The macaques were then challenged with the SARS-CoV-2 delta variant virus at 49 weeks, and more samples were collected at different time points after challenge.

Blood samples collected at 6, 24, and 48 weeks post-vaccination were used to analyze the ability of IgG antibodies in these samples to bind the receptor-binding domains of three different viruses: 1) “ancestral” SARS-CoV-2, which had the exact spike protein antigen encoded in the vaccine, 2) the delta variant, and 3) the beta variant. These latter two had variant spike proteins. IgG antibodies are mostly blood-resident and provide the majority of antibody-based immunity against invading pathogens. IgG levels were highest at 6 weeks after vaccination for all three viruses; they then declined rapidly between 6 weeks and 24 weeks, and more slowly between 24 weeks and 48 weeks. Most IgG detected at 6 weeks bound ancestral virus, with 5.4-fold and 8-fold fewer IgG molecules binding the delta and beta variants, respectively. However, when delta and beta variant-specific IgG antibodies were tested for their ability to block binding between SARS-CoV-2 and its cognate ACE2 receptor, they inhibited almost 100% of binding of both delta and beta variant viruses, suggesting that the antibodies were still functional in preventing infection, in spite of their diminished quantity.

The ability of blood-resident IgG antibodies to neutralize the three respective viruses followed a similar trend, with a gradual decline in neutralizing activity against all viruses by 48 weeks post-vaccination. Interestingly, even though the quantity of total binding and neutralizing antibodies targeting the delta variant decreased over time, the number of antibodies targeting regions associated with neutralization increased. In addition, the binding avidity of antibodies to ancestral virus increased significantly between week 6 and 24 and remained steady through week 48 post-vaccination. In contrast to affinity, which measures the strength of the binding interaction between antigen and antibody at a single binding site, avidity measures the total binding strength of an antibody at every binding site. These two shifts – the increase in the number of antibodies binding targets associated with neutralization and the increase in antibody avidity over time in spite of a decrease in total antibody levels – are suggestive of a maturing immune response that is more focused on viral regions of high immunological relevance. It is noteworthy to mention that the regions associated with neutralization are outside of areas where the variant viruses have accumulated changes in the spike protein, further implying that Spikevax and other SARS-CoV-2 vaccines are just as effective against viral variants as they are against ancestral virus.

Next, the authors analyzed lung wash samples and nasal swabs for delta-binding IgG and IgA antibodies. IgA antibodies are predominantly found in mucus membranes and their fluids, where they protect against invasion by inhaled and ingested pathogens. IgG kinetics in the lung were similar to those observed in the blood – both binding and neutralizing IgG to all three viruses were highest at 6 weeks after vaccination and decreased steadily over time until they were indistinguishable to those observed in unvaccinated animals. In contrast, IgG levels in the nose increased through week 25, plateaued, and remained stable through week 42 post-vaccination. IgA levels in the lung were highest at week 6 post-vaccination, but decreased to levels similar to those observed in unvaccinated animals by week 24. IgA levels in the nose were similar to those in unvaccinated animals at all time points. These results suggest that although SARS-CoV-2 vaccination may not induce a detectable mucosal immune response in the nose, it does induce good initial mucosal immunity in the lung, which is typically the site of severe COVID-19. This immunological difference between the lung and the nose might also explain why SARS-CoV-2 vaccines are more effective at preventing severe disease than at preventing infection.

The authors also analyzed blood samples from vaccinated animals for the presence of SARS-CoV-2-specific memory B cells, which can quickly produce spike-specific antibodies upon subsequent exposure to SARS-CoV-2. At week 6 post-vaccination, about 0.14% of all memory B cells were specific for the ancestral virus, and about 0.09% were specific for the delta variant. In comparison, about 2.5% of all memory B cells were specific for both the ancestral virus and the delta variant, and this high proportion of dual-binding to single-binding cells remained constant through week 42 post-vaccination.

To see whether these vaccine-induced immune parameters are protective after viral challenge, the authors infected the animals with delta variant virus at 49 weeks after the initial immunization. Lung washes and nasal swabs were collected on days 2, 4, 7, and 14 after challenge to monitor viral replication. On day 2 after challenge, vaccinated animals had about 11-fold fewer viral RNA copies per milliliter in their lungs than unvaccinated animals, and these RNA levels declined rapidly over the following days. In contrast, viral RNA levels in unvaccinated animals remained significantly elevated through day 7 post-infection. Viral RNA levels in the nose followed a similar trend; however, their decline in vaccinated animals was not as dramatic as that observed in the lung.

Antibodies to all three viruses in the lungs of vaccinated animals were significantly higher on day 4 after challenge than at week 42 after immunization, suggesting that memory B cell responses to infection were quick and robust. Viral challenge after vaccination also induced both T helper cells, which stimulate B cells to make antibodies, and cytotoxic T cells, which kill virus-infected cells. Analysis of lung tissue also revealed that vaccination prevented lung pathology and protected the lower respiratory tract from severe inflammation after infection.

Perhaps the most interesting observation in the study relates to whether vaccinated individuals who become infected replicate and transmit virus to others. When the authors analyzed lung wash samples for T cells specific for the SARS-CoV-2 N protein, which is not encoded in the Spikevax vaccine, they only found these cells in unvaccinated animals. This suggests that even though it had been one year since vaccination, immunized animals that were then infected did not replicate the challenge virus to a sufficient extent to produce T cells specific for the SARS-CoV-2 N protein – a response that would only be elicited by actual infection with whole virus. In other words, the memory response to the SARS-CoV-2 spike protein induced by the vaccine eliminated incoming virus so quickly that the immune system had no chance to mount a response to the viral N protein encoded in the challenge virus, presumably because the virus was cleared quickly.

In summary, vaccinated animals appear to be better protected from severe disease and to clear virus faster than unvaccinated animals. This result aligns with data published in a previous preprint, which showed that viral RNA levels in delta variant-infected people who had been vaccinated prior to infection declined more rapidly than in people who were not vaccinated. And although monkeys are not human, previous studies assessing the protective efficacy of Spikevax have shown that rhesus macaques are reliably predictive of outcomes in humans, making them a great model for determining the effects of waning antibody levels on long-term protection against SARS-CoV-2 infection.

[Kizzmekia Corbett, a viral immunologist at Harvard who was central to the development of the Moderna mRNA vaccine, was previously a guest on TWiV 670. The preprint described in this post was also discussed on TWiV 824.]

Trial By Error: Losers in NICE Guideline Fight Remain Defiant Despite Public Repudiation of Their Claims

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By David Tuller, DrPH

*For more about the significance of the new NICE guideline for ME/CFS, the blog ME/CFS Skeptic has this excellent summary. Also, psychologist Brian Hughes covers the deep concerns of leading medical groups that the guideline recommends against the Lightning Process.

It is not surprising that esteemed experts whose research has been publicly exposed as a bunch of crap would push back quickly, and that promoters of the debunked work would rally round in defense. That’s what we’ve seen in the wake of Friday’s publication of a new ME/CFS guideline from the UK’s National Institute for Health and Care Excellence (NICE). The document, which reverses the recommendations of a 2007 guideline, specifically advises against the two long-standing first-line treatments—graded exercise therapy (GET) and a specialized form of cognitive behavior therapy (CBT). Both interventions have long been promoted as cures for the underlying condition, based on the theory that patients’ symptoms were perpetuated by a combination of unhelpful illness beliefs and severe deconditioning rather than any organic dysfunction.

Two of the three lead authors of the now-discredited PACE trial, which was once billed as the “definitive” investigation of this approach, offered peevish responses that failed to address NICE’s concerns. In the statements, provided by the Science Media Centre as part of a round-up of comments about the new guideline, they mainly re-bleated past assertions about the benefits of their beloved treatments. (The Science Media Centre’s decision to offer a wide range of comment, rather than just statements overwhelmingly in support of the GET/CBT approach, represents a big shift in how it handles this issue. Perhaps it realizes it needs to cut its losses rather than go down with the GET/CBT ship.)

Professor Trudie Chalder, for example, declared the following: “The NICE guidelines for CFS/ME are at odds with the research evidence.  Researchers from different Institutions [sic] in different countries have found graded exercise therapy and cognitive behaviour therapy to be effective for some patients with CFS.  Evidence has shown they reduce fatigue and improve functioning without harm, if delivered by trained therapists in specialist clinics.”

Poor Professor Chalder! She seems incapable of grappling with the humiliating fact that the NICE review found the evidence for the effectiveness of these interventions on fatigue and physical function, including from the PACE trial, to be of “very low” or merely “low” quality. This was the case whether the research took place in the UK or other countries. As Professor Brian Hughes, a psychologist at the National University of Ireland, Galway, and I documented in this paper in the Journal of Health Psychology, Professor Chalder’s 2020 paper in the Journal of the Royal Society of Medicine on clinic outcomes for patients undergoing CBT relied on serious data misrepresentation in arguing for the effectiveness of the intervention. (Professor Sir Simon Wessely was one the co-authors.)

Given Professor Chalder’s record, nothing she says in this domain can be considered credible. As part of the Science Media Centre round-up, her PACE colleague, Professor Peter White, made equally silly remarks in the same vein. They’re not worth discussing.

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Statement from medical “leaders”

Not to be outdone, other NICE dissenters have issued an incoherent statement of defiance, posted on the website of the Royal College of Physicians under the following headline: “Medical leaders sign joint statement in response to NICE guidance on ME/CFS.” The groups listed, in addition to the Royal College of Physicians, were: the Royal College of Physicians of Edinburgh, the Royal College of General Practitioners, the Royal College of Psychiatrists, the Academy of Medical Royal Colleges, Faculty of Sport and Exercise Medicine, and Faculty of Occupational Medicine

The statement bemoans what it maintains is the guideline’s under-emphasis on “the importance of activity and exercise” in the management of ME/CFS. Among other foolish declarations in pushing this perspective, the “leaders” note the following:

“Graded Exercise Therapy) [sic] as defined in the guidance is not reflective of the personalised paced exercise programmes that are currently used in the NHS and termed GET. These have provided benefit to many patients and should not be discontinued. However, we recognise that the phrase GET is unhelpful and this terminology should be dropped to allow clinicians to work with their patients in a more productive way.”

Let’s parse this weirdness. First, they assert that the NHS is no longer doing GET in the way described in the NICE guideline. The guideline, of course, took its description of GET as well as CBT from PACE and related research, which are explicit about the theoretical bases underlying the interventions and the proper method of implementing them. The framing of GET in the guideline should therefore not be a surprise to anyone. (I wonder how Professors Chalder and White would respond to the news that the NHS has discarded the GET outlined in PACE.)

These medical “leaders” provide no explanation for why NHS services no longer offer GET as proposed and researched by the leading experts in this field. The only logical conclusion would be that they realized it didn’t work. Otherwise, they would presumably have kept doing it in its original form. But if they aren’t offering GET as described in the literature, how do they know what to offer instead? In particular, what is the evidence in favor of the “personalised paced exercise programmes” that the NHS now apparently refers to as GET?

And if the “leaders” acknowledge that the NHS is no longer using GET as described in PACE and related research, presumably because clinicians have realized it doesn’t work, why haven’t they made this absolutely clear to the public before now? Moreover, why are they angry at NICE for highlighting in the new guideline that GET doesn’t work? Apparently they agree that GET shouldn’t be offered; they also agree that the name is tainted and should be dropped. In short, they’re conceding that GET is an inappropriate intervention. So what’s their complaint about the NICE guidance? Why are they throwing a temper tantrum?

Then there is this comment about CBT: “CBT remains a valuable treatment for alleviating symptoms in ME/CFS and services should ensure patients have access to this and other psychological therapies.”

The NICE guideline allows for CBT when it is offered as a supportive rather than a curative intervention, so the beef on the part of the “leaders” appears to be that this modality is not specifically promoted as beneficial. If the “leaders” have evidence that CBT can actually result in recovery, as has been claimed by the PACE authors and others, or plays a “valuable role for alleviating symptoms in ME/CFS,” they should provide it. Significantly, they have not.

A psychological intervention like CBT should probably have the same role in ME/CFS that it has in other chronic medical conditions—to help patients cope with their disease as well as to address co-morbid anxiety, depression and related mental health issues. These “leaders” might believe CBT tackles the underlying illness mechanisms in ME/CFS and deserves an especially prominent place in the treatment arsenal, but they do not seem to have mounted a viable case on that front.

Four of the “leaders” who signed the letter were present at a key roundtable hosted by NICE last Monday to air concerns raised by those objecting to publication.  Yet the minutes of the roundtable, which NICE released along with the guideline, include no indication that these eminent professionals presented robust or indeed any evidence for their categorical claims of benefit from their “personalised paced exercise programmes.” If they possess such data, they have had ample opportunity to make it available. If they don’t, they should stop wasting everyone’s time with empty assertions of benefit. The groups they represent have had as much chance to be involved in the guideline development process as everyone else.

The “leaders” report “disquiet” over NICE’s evaluations of the available evidence and data–even though that evidence and data is not about the “personalised paced exercise programs” they are now touting. As far as this revamped strategy, they seem to expect the right to do whatever they want without having to provide any rationale beyond that they themselves believe it offers benefits. That is not how “evidence-based medicine” is supposed to work. The “evidence-based” approach was intended as an alternative to clinicians’ own positive but often unreliable assessments of the results of favored medical interventions.

These medical “leaders” are jabbering in circles. They don’t like how NICE assessed the evidence, the evidence has nothing to do with what they’re offering anyway, and they have no evidence to support what they’re doing beyond their clinical impressions. That’s pretty much their argument. Either they’re stupid, or they think everyone else is stupid, or they’re trapped in some mental bubble that remains impervious to facts and logic. Their display of petulance is childish, unattractive and anti-scientific, but not surprising.