virology blog
About viruses and viral disease
By David Tuller, DrPH
Adam Lowe, a patient, was one of five lay people on the committee pulled together by Britain’s National Institute for Health and Care Excellence to work on the new ME/CFS guideline. He and I spoke recently on Zoom about his role in the process.
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.â€
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.â€
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.â€
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.
By David Tuller, DrPH
After much drama, the National Institute for Health and Care Excellence (NICE) has finally liberated its hijacked ME/CFS clinical guideline. As many know, in August the agency abruptly called off the planned publication of this new document, which was developed over four years. This decision occurred in the wake of fierce objections from members and allies of the graded exercise therapy/cognitive behavior therapy (GET/CBT) ideological brigades—those who now find themselves on the losing side of a paradigm shift.
In reviewing the relevant research, NICE assessed the quality of the main evidence for the effectiveness of GET and CBT for ME/CFS as of either “very low†or merely “low†quality. In contrast to NICE’s 2007 guidance for what it then called CFS/ME, the new version recommends against psychological and behavioral interventions positioned as curative rather than simply supportive, as well as against interventions based on the theories that patients’ symptoms were perpetuated by deconditioning and/or faulty illness beliefs.
Enabled by NICE’s previous guideline, many health care professionals have profited for years from their purported expertise in this purportedly “evidence-based” therapeutic strategy. Now the agency has changed course and determined this approach to be without merit, leaving these professionals in a bit of a lurch. As Brian Hughes, a psychology professor at the National University of Ireland, Galway, has noted, the history of this field has represented the triumph of “eminence-based†over “evidence-based†medicine. That era is hopefully ending.
Before and after the delay of the August publication date, some of those with reputational and other interests in maintaining the status quo expressed their discontent with the proposed new NICE guideline in blustery and embarrassing public statements. NICE followed up the publication delay with an announcement that it would hold a “round-table†discussion in October in order to allow various parties to air their concerns. That event, which occurred on Monday, was itself a source of much controversy because it represented a departure from NICE’s usual publication processes, among other issues.
Despite the anticipation of fireworks, the roundtable appears to have been rather anti-climactic and largely congenial, according to published comments from participants, with broad support for the version of the guideline produced by the appointed committee. Opponents of the guideline apparently failed to make any convincing arguments for their position. On Thursday, the agency made known that it was planning to publish the document today—as it did. With that, NICE dealt a severe blow to the authority and credibility of the cabal of medical grandees who concocted and promoted the GET/CBT paradigm for this illness in the first place, starting three decades ago.
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So…NICE’s about-face is good news in a field where there often isn’t any. This event is also occurring six years to the week since Virology Blog published my 15,000-word investigation of the PACE trial. At that time, an authoritative repudiation of all the evidence for GET and CBT from a major UK agency would have been inconceivable.
But the two-month delay has been excruciating for the patient community. And no one should view publication of this improved guideline as a panacea or as something that will immediately improve the lives of patients, much less those who have already suffered for years under the prevailing but anti-scientific medical attitudes and beliefs, as a regular Virology Blog commenter (“Lady Shambles”) recently explained in response to a post.
Many others also argue that the new guideline will not prevent the same potentially harmful interventions from being renamed and rebranded in the guise of “supportive†rather than curative care. Invest in ME, which supports biomedical research, today issued a particularly scorching response to NICE about this and other issues raised by publication of the guideline.
It is hard to dispute the validity of many concerns raised by critics, including the tally of the damage caused by long-standing policies. Like any clinical guideline, this one is open to abuse by health care professionals who choose to ignore or misinterpret or mis-apply its recommendations. Nonetheless, as another patient noted on Facebook, the publication is a way to “bank some of the progress†that has been made in correcting the scientific narrative—and can serve as an impetus for seeking related changes in medical practice and research.
by Gertrud U. Rey
On February 27, 2021, the FDA issued an emergency use authorization for a third SARS-CoV-2 vaccine. The vaccine was developed by Janssen Pharmaceutica, a Belgium-based division of Johnson & Johnson, in collaboration with Beth Israel Deaconess Medical Center in Boston. Perhaps the most exciting feature of this new vaccine is that it only requires one dose to be effective in inducing an immune response.
The vaccine is named Ad26.COV2.S because it consists of a human adenovirus vector, with a DNA genome, into which has been inserted the gene that encodes the full-length SARS-CoV-2 spike protein (pictured). Ad26.COV2.S is similar to AstraZeneca’s vaccine, based on a different adenovirus, and with a slightly different version of spike, which is not yet authorized in the U.S. The notion of using a virus as a vector to deliver vaccines to humans is based on the ability of viruses to enter cells by attaching to host cell receptors and releasing their genome into the cell. Upon injection into a vaccine recipient, the vaccine vector should enter cells and serve as a code for host proteins to synthesize the SARS-CoV-2 spike protein from the inserted gene. Ideally, the spike protein will then act as an antigen to prime the immune system to recognize SARS-CoV-2 if it infects the body at a later time.
Adenoviruses are particularly suitable as vectors for delivering foreign genes into cells because they have a double-stranded DNA genome that can accommodate relatively large segments of foreign DNA, and because they infect most cell types without integrating into the host genome. However, because of the prevalence of adenovirus infections in humans, most people have adenovirus-specific antibodies that could bind and neutralize these vectors, thus rendering them less effective at stimulating antibodies to the inserted gene product. AstraZeneca circumvented this issue by using an adenovirus of chimpanzee origin that does not normally infect humans. The adenovirus used to make Ad26.COV2.S (Adenovirus 26) is of human origin; however, when tested, most people have very few antibodies that inactivate this adenovirus, compared to antibodies against other adenoviruses. Thus, potential Ad26.COV2.S recipients are less likely to have pre-existing antibodies to the adenovirus vector itself. To optimize Adenovirus 26 for use as a vaccine vector, Janssen investigators deleted the gene that regulates viral replication, thus ensuring that the virus vector cannot cause an infection in human cells.
During infection, the SARS-CoV-2 viral particle fuses with the host cell membrane; a process that is mediated by two main events: 1) a structural rearrangement of the spike protein from its pre-fusion conformation; and, 2) cleavage of the spike protein by a cellular enzyme called furin. Based on the knowledge that the pre-fusion, uncleaved form of spike is more stable and immunogenic, Janssen investigators also inserted two mutations into the spike gene: one that locks the translated spike protein into its pre-fusion conformation, and one that prevents its cleavage by furin.
The FDA’s decision to issue an emergency use authorization for Ad26.COV2.S was based on safety and efficacy data from an ongoing Phase III clinical trial done in 39,321 participants who received either a single dose of Ad26.COV2.S or a placebo control. The trial was randomized, meaning that participants were randomly assigned to the experimental group receiving the Ad26.COV2.S vaccine, or the control group, so that the only expected differences between the experimental and control groups were the outcome variables studied (safety and efficacy). Randomizing trial participants eliminates unwanted effects that have nothing to do with the variables being analyzed. The trial was also double-blinded, meaning that neither the investigators nor the subjects knew who was receiving a particular treatment. Double-blinding leads to more authentic conclusions because they reduce researcher bias.
The basic findings of the trial were as follows:
The apparently reduced efficacy of Ad26.COV2.S compared to the Moderna and Pfizer vaccines has led to considerable public skepticism. However, this is an unfair comparison for several reasons. Ad26.COV2.S was tested at a time when more variants were in circulation, including in places where the Moderna/Pfizer vaccines are thought to be less effective against locally circulating variants. Some limited data also suggest that Ad26.COV2.S might protect from asymptomatic infection and may thus prevent transmission from vaccinated individuals to non-vaccinated individuals. Although there is some evidence to suggest that the Pfizer vaccine has a similar effect, no such data exist yet for the Moderna vaccine.
The most critical measure of a vaccine’s efficacy is how well it prevents severe disease, hospitalizations, and deaths, and in this regard, all three vaccines are comparable. Moreover, Ad26.COV2.S has at least two advantages over the Pfizer/Moderna vaccines: 1) it does not require a freezer and can be stored in a refrigerator for up to three months; and, 2) it can be administered in a single dose. This will increase vaccine uptake, because people won’t have to get two shots and/or remember to get the second shot. It also makes it easier to immunize people with limited access to healthcare, such as the homeless and people living in remote areas. When all these factors are considered together, it is clear that Ad26.COV2.S will be a crucial additional tool in the fight against this pandemic.
by Gertrud U. Rey
Antibodies are large proteins that are made by B cells of the adaptive immune system. Most people think that antibodies function only as a whole molecule, but some of the individual fragments of an antibody can also bind and neutralize antigens. 
An antibody consists of two heavy chains and two light chains that assemble into a Y-shaped structure (left side of Figure). The stem of the Y is known as the “fragment crystallizable” (Fc) portion and is composed of two heavy chains. The two arms of the Y are known as the “fragment antigen-binding” (Fab) portions and are each composed of one heavy chain and one light chain. As its name suggests, the top half of each Fab fragment is the antigen-binding region of the antibody, and it is variable – meaning that it varies between antibodies that are produced by different B cells. The bottom half of each Fab fragment and the entire Fc region are constant, meaning that they are identical in all antibodies of the same isotype, but differ in antibodies of different isotypes. For example, the constant regions are identical in all IgG antibodies but differ between IgG and IgA antibodies.
In an effort to identify anti-SARS-CoV-2 antibodies suitable for preventing and treating SARS-CoV-2 infection, the authors of a recent publication screened 100 billion different anti-SARS-CoV-2 antibody candidates for their ability to bind and/or neutralize SARS-CoV-2. This eventually led to the discovery of “ab8,” an antibody fragment consisting of a variable heavy (VH) region and having particularly potent SARS-CoV-2 binding specificity and neutralization activity. To increase the binding avidity of ab8 (i.e., the stability of its interaction with an antigen) and extend its longevity in the human body, the authors fused this fragment to the Fc domain of human IgG1, an abundant and stable type of human antibody. This produced the molecule hereinafter referred to as “VH-Fc ab8″ (right side of Figure).
The authors found that VH-Fc ab8 can bind various conformations of the SARS-CoV-2 spike protein, including when the spike protein is bound to a cell surface. VH-Fc ab8 can also bind to and neutralize six different SARS-CoV-2 isolates having different amino acid changes in the receptor-binding domain, suggesting that it is broadly cross-reactive. Notably, it does not bind to human cells, meaning that it does not seem to interfere with normal cellular functions.
As a next step, the authors evaluated the ability of VH-Fc ab8 to prevent SARS-CoV-2 infection in mice. If given to mice before they were infected with SARS-CoV-2, VH-Fc ab8 inhibited viral replication at all doses tested, but it only neutralized virus at the highest dose of 36 mg/kg. Although these results were encouraging, it is often difficult to interpret data obtained in mice in terms of clinical relevance in humans, because mice don’t develop the COVID-19-related disease pathologies observed in humans. Hamsters more closely imitate human SARS-CoV-2 infection in the lung, suggesting that they could be a useful mammalian model for COVID-19. VH-Fc ab8 caused significantly reduced levels of infectious virus in the lung, nasal mucosa, and saliva of hamsters when administered one day before (i.e., “prophylactically”) or six hours after SARS-CoV-2 infection (i.e., “therapeutically”) compared to untreated control animals, suggesting that it could be used to both prevent and treat SARS-CoV-2 infection. Although VH-Fc ab8 led to greater reduction of virus levels when given prophylactically than when given therapeutically, therapeutic administration still led to significantly decreased viral loads in treated animals compared to untreated control animals, even at very low doses. VH-Fc ab8 not only alleviated pneumonia and reduced lung viral loads in hamsters, but it also reduced virus shedding in the upper airway, which could help with reducing transmission.
The authors also found that when they gave hamsters the same dose of either VH-Fc ab8 or IgG1 ab1 – a full-sized version of the antibody, and then examined their concentrations in the serum five days later, levels of VH-Fc ab8 were significantly higher than those of the full-sized antibody. This suggests that the systemic distribution of VH-Fc ab8 is more long-lived than that of a full-sized antibody.
Although small animal models can provide key insights into the pathogenic mechanisms of viral infections, they are often poor predictors of human disease outcomes. The therapeutic timeline followed in the hamster experiments (i.e., administration of VH-Fc ab8 six hours after infection) would also be difficult to reproduce in humans because therapeutic drugs are not usually administered until well after symptom onset. Therefore, it would be difficult to determine whether the therapeutic effect of VH-Fc ab8 observed in hamsters would be the same in humans.
That being said, there are clear advantages to using antibody fragments instead of whole antibodies. Their small size allows them to penetrate more efficiently to sites of infection and bind antigens more easily and with more specificity. Smaller molecules also diffuse more easily through tissues, meaning that they could be administered by routes other than injection, such as by inhalation. Furthermore, because the molecular weight of VH-Fc ab8 is only about half that of a full-sized antibody, smaller quantities would be needed to obtain the same number of molecules, meaning that antibody fragment therapeutics could be more easily mass-produced.
There is no question that we are in dire need of an effective therapeutic drug to treat SARS-CoV-2 infection. If the results observed in these animal experiments can be duplicated in humans, VH-Fc ab8 would be an attractive option for both treating and preventing SARS-CoV-2 infection.
In this mid-week edition, identifying flawed research before it becomes dangerous, Michigan governor tells America to mask-up, Pfizer mRNA vaccine gets $1.95 billion from Warp Speed, preliminary phase I/II results of the ChAdOx1 SARS-CoV-2 vaccine, answers to listener questions.
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