virology blog – Page 2

Trial By Error: NICE Squares Off Against Royal College Bullies Over New ME/CFS Guidelines

19 August 2021 by David Tuller

By David Tuller, DrPH

For many years, campaigners for psycho-behavioral interventions for ME/CFS have accused patients who objected to the research as being anti-scientific zealots. It was always a ridiculous charge, but developments this week have made it clear, if there was any doubt, that these entitled bullies are the ones immune to the actual evidence.

The National Institute for Health and Care Excellence (NICE), the British organization that develops clinical guidelines, began the process of revising its outdated 2007 ME/CFS recommendations four years ago. It selected an excruciatingly balanced committee, with representatives from various sides of the debate, including several patients. It would not be possible to argue convincingly that the process was stacked against the advocates of graded exercise therapy and cognitive behavior therapy, the two standard treatments.

Estimate of infectiousness during COVID-19

12 August 2021 by Vincent Racaniello

Understanding the transmission of SARS-CoV-2 is complicated by the large numbers of presymptomatic, asymptomatic, and mildly symptomatic (PAMS) patients. The reproductive number, R0, is a measure of population-level dynamics, but it cannot provide information on infectiousness of different groups such as PAMS subjects; when peak infectiousness occurs; and the effect of intrinsic properties of the virus. However information on infectiousness can be provided by a study of viral RNA load and infectivity in cell culture.

A study of 25,381 German COVID-19 cases was done to provide information on infectiousness during the course of infection. These included 6110 PAMS cases, 9159 hospitalized patients, and a series of times samples from hospitalized patients. Viral RNA loads – defined as RNA copies per swab – were determined by RT-PCR. The association between viral RNA load and probability of virus isolation in cell culture was estimated by using previously determined cell culture isolation data.

The results show that PAMS subjects have viral RNA loads (pictured) and predicted infectiousness, at the first positive test, slightly less than those of hospitalized patients. Children had similar viral RNA loads and predicted cell culture infectivity.

A small fraction of individuals’ first-positive viral RNA loads – 8%- had 10e9 RNA copies per swab. This observation is in line with previous findings that 15% of index cases are responsible for 80% of transmission, and that 8-9% of infected individuals carry 90% of the total viral load.

Time-course analysis revealed that viral RNA load peaks 1 to 3 days before onset of symptoms. From this peak, viral RNA loads decline 0.17 log10 units per day. Previous studies have shown that infectious virus is typically not recovered in cell culture beyond 10 days from symptom onset.

This study also examined viral RNA loads in 1533 patients with alpha variant infections. Compared with non-alpha infections, patients infected with the alpha variant had 10 times higher viral RNA loads and a 2.6 fold higher estimated cell culture infectivity. However, the impact of an increase in viral RNA load is, as the authors write, ‘dependent on context’ and the increase in cell culture infection probability is a ‘proxy indication of potentially higher transmissibility’. Complicating this analysis is the possibility that the correlation of viral RNA loads with cell culture infectivity might differ among variants.

The most important outcome of this study is that PAMS subjects – who in this study were tested at walk-in centers – are as infectious as hospitalized patients. As these individuals circulate in the community they can clearly trigger outbreaks of infection.

Trial By Error: The Times Fact-Checks BMJ on NICE Committee; My Letter to BMJ’s Fiona Godlee

10 August 2021 by David Tuller

By David Tuller, DrPH

It is not often that a major news organization fact-checks BMJ, a leading medical publisher, in real time. But that’s what happened last week when The Times pushed back against biased BMJ reporting about the committee charged by the UK’s National Institute for Health and Care Excellence (NICE) with developing a new clinical guidance for ME/CFS. This isn’t the first time The Times has seen through the propaganda campaign emanating from those with financial and reputational interests in maintaining the GET/CBT approach despite widespread rejection of its theoretical and scientific underpinnings.

Trial By Error: Three CBT/GET Proponents Quit NICE ME/CFS Guidance Panel as Publication Date Nears

7 August 2021 by David Tuller

By David Tuller, DrPH

The new ME/CFS clinical guidance from the UK’s National Institute for Health and Care Excellence (NICE) is finished—and is to be publicly released on August 18th. In the meantime, this final version has been sent to registered stakeholders—even as three of the 21 members of the committee responsible for the guidance have stepped down without public explanation, per an “exclusive” report on BMJ’s news site. All three quitters represented the wing of the committee that promoted the purported benefits of cognitive behavior therapy (CBT) and graded exercise therapy (GET) as core treatments.

Heterologous Vaccine Regimens Might be Better

5 August 2021 by Gertrud U. Rey

by Gertrud U. Rey

Have you ever wondered if you can “mix and match” SARS-CoV-2 vaccines? For example, would it be ok to boost a first dose of the vaccine produced by AstraZeneca with a dose of the vaccine produced by Pfizer/BioNTech? The latest science shows that such a vaccine regimen actually induces a stronger immune response than a regimen consisting of two doses of the same vaccine.

The occasional incidence of thrombosis in people under the age of 60 after receiving an adenovirus-vectored vaccine like the ones made by AstraZeneca and Johnson & Johnson has prompted several European governments to recommend the use of these vaccines only in people over 60. Because many people under 60 had already been vaccinated with a first dose of the AstraZeneca vaccine and still needed a second dose, they had to decide whether they should continue their regimen with another dose of the same vaccine (i.e., a homologous regimen), or receive an mRNA vaccine instead (i.e., a heterologous regimen).

In an effort to evaluate the efficacy of a heterologous SARS-CoV-2 vaccine regimen, the authors of this Brief Communication engaged the participants of an ongoing clinical trial, which aims to monitor the immune responses to SARS-CoV-2 in health care professionals and individuals with potential exposure to SARS-CoV-2. All study participants had already received a first dose of the AstraZeneca vaccine (referred to as “ChAd” in the study) and were given the option of receiving a second dose of the same vaccine or a dose of Pfizer/BioNTech’s mRNA vaccine (referred to as “BNT”). Although both of these vaccines encode the gene for the full-length SARS-CoV-2 spike protein, it is housed slightly differently. In the ChAd vaccine, the spike protein is encoded in an adenovirus vector of chimpanzee origin, while in the BNT vaccine it is surrounded by a lipid nanoparticle.

Out of the 87 individuals who participated in the study, 32 chose a second dose of ChAd and 55 chose to be vaccinated with BNT instead. Participants who chose a homologous ChAd/ChAd regimen received their second dose of ChAd on day 73 after the initial dose and donated a blood sample for analysis 16 days later. Participants who chose a heterologous ChAd/BNT regimen received their dose of BNT 74 days after their initial ChAd dose and donated a blood sample 17 days later. All results obtained from the analyses of the blood samples from these two groups were compared to results obtained from a group of 46 health care professionals who had been vaccinated with two doses of BNT (i.e., a homologous BNT/BNT regimen).

Briefly, the findings were as follows. Relative to the antibody levels induced by the first dose, homologous boosting with ChAd led to a 2.9-fold increase in IgG antibodies against the SARS-CoV-2 spike protein. IgG antibodies are mostly present in the blood and provide the majority of antibody-based immunity against invading pathogens. In contrast, heterologous boosting with BNT led to an 11.5-fold increase in anti-spike IgG, within the range observed in BNT/BNT-vaccinated individuals. A similar pattern was observed with anti-spike IgA antibodies, which are predominantly found in mucus membranes and their fluids. Boosting with BNT induced significantly higher increases in anti-spike IgA than did boosting with ChAd, suggesting that a heterologous boosting regimen induces better antibody responses. Interestingly, although the booster immunization induced an increase in neutralizing (i.e., virus-inactivating) antibodies in both vaccination groups, only heterologous ChAd/BNT vaccination induced antibodies that neutralized all three tested variants (Alpha, Beta, and Gamma), similar to what was observed in BNT/BNT vaccine recipients.

The authors also analyzed the effect of the two different boosting regimens on spike-specific memory B cells, which circulate quiescently in the blood stream and can quickly produce spike-specific antibodies upon a subsequent exposure to SARS-CoV-2. All vaccinees from both the ChAd/ChAd and ChAd/BNT groups produced increased levels of spike-specific memory B cells after receiving their booster shot, with no significant differences observed between the two groups. These results emphasize the importance of booster vaccination for full protection from SARS-CoV-2 infection.

ChAd/BNT recipients also had significantly higher levels of spike-specific CD4⁺– and CD8⁺ T cells compared to ChAd/ChAd recipients. CD4⁺T cells are a central element of the adaptive immune response, because they activate both antibody-secreting B cells and CD8⁺ T cells that kill infected target cells. Compared to the ChAd/ChAd regimen, ChAd/BNT vaccination also induced significantly increased levels of T cells that produce spike-specific interferon gamma – a cytokine that inhibits viral replication and activates macrophages, which engulf and digest pathogens. Overall, these results suggest that a heterologous ChAd/BNT regimen induces significantly stronger immune responses than a homologous ChAd/ChAd regimen.

The study did have several limitations. First, it was not a randomized, placebo-controlled trial where each participant was randomly assigned to an experimental group or a control group. Randomizing trial participants eliminates unwanted effects that have nothing to do with the variables being analyzed, so that the only expected differences between the experimental and control groups are the outcome variable studied (efficacy in this case). Subjects in a control group receive a placebo – a substance that has no therapeutic effect, so that one can be sure that the effects observed in the experimental group are real and result from the experimental drug. Second, the authors were unable to test the antibodies for their ability to neutralize the Delta variant, which has recently become the predominantly circulating variant in many parts of the world. Third, the study mostly included young and healthy people, making it difficult to extrapolate the data to other specific patient groups outside of this category. Fourth, the data only show the results of assays performed in vitro, which may not necessarily manifest a clinical significance. Extended studies aimed at determining the practical importance of the observed immune responses are needed to validate the relevance of these responses.

Despite its limitations, the study provides information that could have some valuable practical implications. Most of the currently approved SARS-CoV-2 vaccine regimens involve two doses of the same vaccine. However, access to two doses of the same vaccine may be limited or absent under some circumstances, thus necessitating the use of a different type of vaccine to boost the first dose.

[For a more in-depth discussion of this study, I recommend TWiV 782.]

Trial By Error: Neurology Journal Fixes False Claim in MUS Paper–But Fails to Publish a Correction Notice (Ironically, I Have Added a Correction to the Post!)

31 July 2021 by David Tuller

By David Tuller, DrPH

UPDATE: August 4, 2021

Dr Villemarette-Pittman, the managing editor of Journal of the Neurological Sciences, has informed me that she has learned from Elsevier that a corrigendum has in fact been written and will be published in the near future. She also informed me that she plays no role in deciding on or setting policy about corrections and corregendi, and when or how they are published. I am very glad to hear about the corrigendum. Had I been informed earlier in the cycle of e-mail exchanges that the lack of a corrigendum did not mean that none was forthcoming and that a response from Elsevier was being sought, I would have written the blog post differently and/or updated it sooner. Dr Villemarette-Pittman had responded on behalf of the journal to my initial e-mail about the error, so I assumed she understood the practices and policies around corrections and corregendi. I apologize to Dr Villemarette-Pittman for having made that mistaken assumption.

Paul and the Mosquitos

30 July 2021 by Vincent Racaniello

From the authors of Paul Has Measles and Paul Stays Home comes Paul and the Mosquitos, an illustrated book for children about mosquito-borne diseases.

In his camp, Paul and his friends discuss which is the most dangerous animal of all. They would never have imagined it would be the mosquito. Why are they dangerous and what can we do to prevent the diseases transmitted by them?

Paul and the Mosquitoes is written by Susana López, Selene Zárate, and Martha Yocupicio, with illustrations by Eva Lobatón.

A pdf of Paul and the Mosquitos can be downloaded free of charge here.

T cells will save us from COVID-19, part 3

29 July 2021 by Vincent Racaniello

In the two previous installments (one, two) of what has now become my praise of T cells, I explained that the SARS-CoV-2 protein sequences recognized by T cells do not change, likely explaining why vaccines prevent serious disease and death caused by any variant. Today I will explain that virus-specific T cells appear a week after mRNA vaccination when neutralizing antibodies are weakly detectable. Their presence is likely responsible for vaccine-mediated protection against severe disease.

Since the first COVID-19 vaccines were tested in clinical trials, much has been made of their ability to block infection. At ten days after the first vaccine dose, clear protection against severe disease is observed. But at this early time, neutralizing antibodies can barely be detected. That job is likely being done by T cells, the other arm of the adaptive immune response.

T lymphocytes come in two broad types: CD8+ and CD4+. The former, also known as cytotoxic T lymphocytes (CTLs) can recognize a virus infected cell and kill it (pictured). The latter T cells produce cytokines that are important for maturation of both CTLs and B cells, the antibody-producing cells. The importance of antibody versus T cells in controlling infection depends on the virus. For many viruses, antibody can block infection, but T cells are important for recovery. In COVID-19, antibodies rise late in the course of infection, when virus titers are already declining. This observation is in line with the resolution of infection by T cells.

People with agammaglobulinemia, who cannot make antibodies, or who have been depleted of B cells do not have a serious course of COVID-19, further supporting a role for T cells in preventing severe disease.

During the trials of mRNA vaccines it was observed that protection against severe COVID-19 arose at 10 days after the first inoculation, a time when neutralizing antibodies are barely detectable in serum. The logical candidate for this effect is the T cells.

To address this question, a group of mRNA vaccine recipients were sampled at different times after the first and second doses. CD8+ T cells in blood were examined for the ability to recognize a few spike-specific epitopes. A rapid and substantial induction of CD8+ T cells in these individuals was observed beginning at 6-8 days after the first vaccine dose. At this time, neutralizing antibodies in sera of these subjects were barely detectable. CD8+ T cell numbers are substantially increased by the second vaccine dose, which also leads to much higher levels of neutralizing antibodies. CD4+ T cells are also detected after the first vaccine dose and likely coordinate the expansion of CD8+ T cells and B cells.

mRNA vaccination also induces spike-specific memory B and T cells which circulate for at least several months. Their exact longevity remains to be determined by longer term studies.

The gradual escape of multiple variants of concern from neutralization by sera from vaccinated individuals has been met with alarm by public health officials. At least one prominent leader has suggested that the virus might even mutate so as to escape vaccine protection. An even cursory examination of the facts reveals otherwise. Despite reduced neutralization by vaccine-induced antibodies, vaccine recipients are still protected from severe disease and death by all variants. In contrast to changing B cell epitopes, T cell epitopes do not change in any variant. Furthermore, virus-specific T cells are induced early after the first mRNA vaccine dose, and confer protection against severe COVID-19 at a time when neutralizing antibodies are barely detectable. These observations indicate that T cells will save us from COVID-19.

In vaccinology, the correlate of protection refers to what is needed – antibodies or T cells – to protect from infection or disease. High levels of antibodies appear to correlate with protection against infection by SARS-CoV-2. However, when antibody levels decline, as they always do after infection or vaccination, infection can no longer be prevented. In this case, protection against severe disease and death is accomplished by T cells.

Trial By Error: Tack and I Write to Psych Medicine; Struthers Writes to Medical Research Council

24 July 2021 by David Tuller

By David Tuller, DrPH

A recent study of cognitive behavior therapy (CBT) for patients with “persistent physical symptoms” (PPS), a category alsocalled “medically unexplained symptoms,” reported null results for its primary outcome. These null results were not mentioned in the conclusion of the abstract, which instead focused on minimal reported benefits for a minority of secondary outcomes. This is not cool! The study was published in Psychological Medicine—a journal with close ties to the PACE investigators and other members of the CBT ideological brigades.

Trial By Error: CBT Model of Medically Unexplained Symptoms, Explained; CBT Trial for Q-Fever Fatigue

22 July 2021 by David Tuller

By David Tuller, DrPH

As I have recently written, four major clinical trials of CBT for so-called MUS have documented the opposite of what the investigators hoped to prove. In fact, the evidence from this research suggests that CBT is not an effective treatment for these conditions. That hasn’t stopped these investigators from claiming otherwise, of course. As my earlier post indicated, they have deployed a range of methodological, statistical and rhetorical strategies to obfuscate or downplay their poor results. Three of these studies were based at King’s College London, and one—the now-discredited PACE trial—at Queen Mary University of London.

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