Emmie de Wit joins TWiV to explain her work on the pathogenesis of infection with SARS-CoV-2 in rhesus macaques, including studies on remdesivir and a vaccine candidate.
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By David Tuller, DrPH
I’ve been writing about so-called “medically unexplained symptoms,” or MUS, for the last couple of years. Much of that has come in the form of critiques of specific studies making excessive claims about the healing powers of cognitive behavior therapy.
Recently, a blogger named Goodelf has posted a couple of revealing posts about the overall approach to MUS in the UK, especially about how proponents of the concept have presenting data in misleading ways. Both articles have been posted on the Opposing Mega site, originally established a few years ago to counter a stupid proposal from the then-leadership of the CFS/ME Research Collaborative. The first article was about a seminal study on the supposed prevalence of MUS and on rates of misdiagnosis.
I’ve posted below the opening of the second article, which elaborates on the issue and is titled “A Letter to Jeremy Hunt.”
Daniel Griffin provides a clinical update on COVID-19, then we review an Ad5 vectored SARS-CoV-2 vaccine, reports on remdesivir and hydroxychloroquine, a drug repurposing study, why some patients infect many others, reducing viral transmission, and much more, including listener email.
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Jon Yewdell returns to explain studies on detection of antibodies and T cell epitopes in patients who have recovered from COVID-19.
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UPDATE: I sent the following correction to Dr Choonara shortly after sending the letter of concern.
Dear Dr Choonara:
I wanted to make a slight correction in point #3 below. The first sentence should have read: “Why was the outcome of recovery not mentioned in the trial registration and statistical analysis plan yet still highlighted in the paper?” As I previously reported on Virology Blog, the outcome of recovery was mentioned in the protocol but not in the other two trial documents. I apologize for the error.
Best–David
David Tuller, DrPH
Senior Fellow in Public Health and Journalism
Center for Global Public Health
School of Public Health
University of California, Berkeley
Berkeley, California, USA
**********
In recent weeks, the Norwegian tabloid Dagbladet has published a series of articles about ME, which it also calls CFS/ME. These articles have promoted the use of the Lightning Process as an intervention, criticized patients and the Norwegian ME Association for expressing opinions about the Lightning Process and cognitive behavior therapy, and engaged in multiple other stupidities. The first articles ran a couple of weeks ago. The most recent one ran today.
Small animal models (mice, ferrets, hamsters) are essential for understanding how SARS-CoV-2 causes disease and for pre-clinical evaluation of vaccines and antiviral therapeutics. One promising model has been developed by modifying SARS-CoV-2 so that it binds to murine ACE2.
Laboratory mice cannot be infected with SARS-CoV-2 because the viral spike glycoprotein (illustrated) does not bind to murine ACE2, the ortholog of the human receptor. Mice transgenic for the human ACE2 gene, produced after the SARS-CoV outbreak, can be infected with SARS-CoV-2, but the pathogenesis does not resemble that observed in humans. For example, mortality in infected mice appears to be a consequence of replication in the central nervous system, not in the respiratory tract. The altered pathogenesis might be due to improper expression patterns of the ACE2 gene.
In another approach to producing a mouse model for COVID-19, the spike glycoprotein of SARS-CoV-2 was modified so that it efficiently binds murine ACE2 protein. Only two amino acid changes in the S protein were required to allow infection of cells that produce murine ACE2 without affecting reproduction in monkey cells.
Upon intranasal infection of young mice, virus replication was detected in the upper and lower airways and was accompanied by mild to moderate disease. In contrast, after inoculation of older mice, viral replication was not only detected in the upper and lower tract but was associated with lung inflammation and loss of pulmonary function. The age-dependency of disease mimics what is observed in humans.
As a proof of principle, the mouse model was used to evaluate efficacy of a vaccine and antiviral. After vaccination of mice with a Venezuelan equine encephalitis vector carrying the SARS-CoV-2 spike protein gene, reduced virus replication in lung and upper respiratory tract was observed after challenge compared with control mice. Furthermore, prophylactic and therapeutic administration of IFN-lambda-1 reduced virus titers in the lung compared with untreated mice.
This mouse model is attractive because it does not require the development of genetically altered animals. However it is not a perfect model because there are likely differences in tissue distribution of ACE2 in mice and humans which could affect disease outcomes. Whether this difference has an impact on the usefulness of the mouse model remains to be seen. Meanwhile other mouse models are being developed which might have other advantages: for example the production of human ACE2 in mice by using adenovirus-associated virus vectors.
I have always made it clear that I pay attention when smart patients assess bad research. That’s how I stumbled into this whole mess in the first place–by reading what patients were writing about the PACE trial. (In that case, I at first dismissed the concerns when I read about how participants could get worse and still be counted as recovered. I figured patients must have it wrong. I knew no credible journal could have published such a study–much less failed to retract it when the problem had been pointed out.)
I have recently written a few posts–here, here and here–about a study in BMJ Paediatrics Open that appears to be marred by multiple methodological and ethical problems. This is certainly not a one-time occurrence when it comes to BMJ journals. Last week, I sent a letter to the study’s senior author inviting him to send me his response for posting in full on Virology Blog. I have not heard back.
Raul Rabadan joins TWiV to explain the use of computational biology to demonstrate how recombination and mutation led to emergence of SARS-CoV-2.
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Paul Has Measles is a free children's book about viruses and vaccines available in 16 languages (