On this mid-week edition, does it matter that SARS-CoV-2 is mutating, seasonal coronavirus immunity is short-lived, another bogus claim that the virus was produced in a laboratory (it came from Nature), and answers to listener questions.

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by Helen Stillwell

Recently, a Phase 3 trial investigating a COVID-19 vaccine (AZD1222) being developed by AstraZeneca and the University of Oxford was put on hold in the US following a report of an adverse event in a study participant in the U.K. (Feuerstein 2020). One of the predominant vaccine candidates against SARS-CoV-2, AZD1222 is a chimpanzee adenovirus-vectored vaccine expressing the SARS-CoV-2 spike protein. This technology has yet to be used in an FDA-approved vaccine; however, it has been widely tested in early phase trials for a variety of viruses, such as Ebola virus. 

The UK participant that triggered the study’s hold presented with neurological symptoms that were diagnosed as transverse myelitis (TM). TM is a rare inflammatory disorder that involves the spinal cord and manifests as rapid onset weakness, sensory deficits, and bowel/bladder dysfunction (Simone & Emmady 2020). The disease can persist for as little as 3 to 6 months or result in permanent debilitation. 

TM typically arises idiopathically — without a known cause; however, it can also arise post-infection. TM has been reported following infection with enteroviruses, West Nile virus, herpes viruses, HIV, human T-cell leukemia virus type I (HTLV-1), Zika virus, and others (Simone & Emmady). TM is an autoimmune condition that results when one’s immune system is unable distinguish between ‘self’ antigen and infectious antigen. In eliciting a host immune response through the presentation of a viral antigen, in some cases, vaccines initiate the autoimmune cascade, resulting in diseases such as TM (Levin et al. 2009). Indeed, a systematic review of the literature citing TM associated with vaccination identified 37 reported cases between 1970 and 2009.

Viral infection may induce autoimmunity through several mechanisms: molecular mimicry between viral antigens and ‘self’ antigens, epitope spreading by which viral antigens accelerate an existing autoimmune response through increased inflammation, or the polyclonal activation of B lymphocytes or bystander activation resulting in increased cytokine production and the expansion of self-reactive T-cells (Levin et al. 2009).

Clinically, however, it is difficult to say for certain whether an environmental stimulus such as vaccination is the direct cause of an autoimmune condition. In some cases, an autoimmune condition may have been developing slowly overtime and had yet to present symptoms. 

The AstraZeneca trial was halted following this incident to allow for a comprehensive examination of the case, something that is not uncommon in Phase 3 clinical trials. In any clinical trial, unexpected illness emerges among study participants – whether that illness is a result of the study drug is subject to an extensive review of the case and whether there were any other factors involved that might have contributed to the outcome. Therefore, the fact that the study was paused due to an adverse event does not necessarily say anything in particular about the vaccine’s safety or efficacy at this point in time. While another study participant also reported neurological symptoms earlier this summer, the patient was later diagnosed with multiple sclerosis which was found to be unrelated to vaccine administration (Feuerstein 2020). 

An evaluation of the case by an independent safety committee and regulatory officials determined that it would be safe to resume the trial in the UK (Loftus 2020). No specific information on the decision was offered to protect the confidentiality of the affected participant; however, the review must have revealed information that compelled officials to conclude that the likelihood that the vaccine had caused the patient’s TM was very low.

References

Simone CG, Emmady PD. Transverse Myelitis. [Updated 2020 Aug 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan.

Feuerstein A. COVID-19 Vaccine Trial Participant Had Serious Neurological Symptoms, But Could Be Discharged Today, AstraZeneca CEO Says. STAT News. (2020). https://www.statnews.com/2020/09/09/astrazeneca-covid19-vaccine-trial-hold-patient-report/.

Levin NA, Kivity S, Szyper-Kravitz, Shoenfeld Y. Transverse myelitis and vaccines: a multi-analysis. Lupus. (2009) 18: 1198-1204. 

Loftus P. AstraZeneca COVID-19 Vaccine Trials Resume in U.K. WSJ. (2020). https://www.wsj.com/articles/astrazeneca-covid-19-vaccine-trials-resume-in-the-u-k-11599922981.

By David Tuller, DrPH

This morning (Wednesday) I gave an informal online talk about the piece of crap known as the PACE trial to a small group of UK doctors, researchers and others. The group had been pulled together by Paul Garner, a physician and professor of infectious diseases at Liverpool School of Tropical Medicine. Garner has written several widely read blog posts for BMJ about his struggles with profound exhaustion and other long-Covid symptoms.

In those posts, Garner has expressed sympathy for the plight of people with ME and their challenges in finding adequate medical treatment. Those experiences triggered his interest in the PACE saga–about which I know a little bit.

As sometimes happens, I got a bit, uh, energized while I discussed the PACE trial. It’s possible I dropped a four-letter word as I explained how the outcome thresholds were weakened so much that people could get worse on key measures and still be considered “recovered.” (Or “back to normal,” as one of the PACE investigators falsely declared at the 2011 press conference presenting the first results.)

In the talk, I expressed dismay that the study remains in the medical literature even though 13% of participants met a primary outcome threshold at baseline. If disclosed before publication, that bizarre statistical anomaly would or should have caused immediate rejection of any manuscript. I said the paper, in my opinion, qualified as research misconduct—something I would say about any paper in which the investigators did not disclose that 13% of their participants had met an outcome threshold at baseline.

That a study including this feature passed peer review is hard to understand. Lancet editor Richard Horton, who professes outrage at bad research published in other journals yet thinks highly of PACE, has refused to disclose anything about the reviews. I assume they would, if released, cause some embarrassment, given the many flaws that marred the published paper. Two years ago, more than 100 experts from around the world signed Virology Blog‘s open letter to Horton, which cited the study’s “unacceptable methodological lapses” and requested an independent investigation.

I suggested some of the logic on display in the defense of PACE had a Trumpian quality to it. I also suggested that science can’t work if people who raise legitimate concerns–such as that participants in PACE could be “disabled” and “recovered” simultaneously on key measures–are dismissed as hysterics and dangerous climate-change deniers. I noted that MP Carol Monaghan had called PACE “one of the biggest medical scandals of the 21st* century.” I said I thought it was likely one of the biggest medical scandals of the millennium–although it’s kind of early for a definitive assessment. [*I originally wrote 20th century. Oops! Time flies!]

I didn’t prepare a slide presentation–just sent out a one-pager with a few salient details and thoughts. We didn’t discuss the PACE authors’ extensive ties to disability insurance companies and government agencies—I meant to bring it up, but I forgot! So I made sure to highlight these conflicts of interest in a follow-up e-mail.

The one-pager I sent the participants concluded with the following points:

*Why have all levers of authority in UK science endorsed this study—journals, NHS, Cochrane, etc.? Why hasn’t it been dealt with? Why have patients been so poorly treated?

*Other themes: gaslighting, research misconduct, “eminence-based medicine”

By David Tuller, DrPH

Doctors in UK urge caution on long-Covid exercise advice

Despite BMJ’s current dereliction of key editorial oversight responsibilities, it has provided a forum for members of the medical community with Covid-19 and post-Covid symptoms to express their strong views.

The reference to current dereliction of key editorial responsibilities involves a case I and others have raised repeatedly with BMJ in recent months. The concerns relate to a study of cognitive behavior therapy and music therapy for chronic fatigue in adolescents after acute EBV, which was published in April by BMJ Paediatrics Open. More than three months ago, four colleagues and I alerted the journal itself, along with BMJ’s editorial leadership, that one of two peer reviewers flatly stated in his review that he had not read “beyond the abstract”—in other words, he did not actually read the study.

[continue reading…]

Daniel Griffin provides a clinical report on COVID-19, including vaccines, Alan summarizes a vaccine webinar on the most advanced US trials, a nidovirus from snapping turtles, longevity of memory B cells in recovered patients, and listener email.

The British people can face any misfortune with fortitude & buoyancy as long as they are convinced that those in charge of their affairs are not deceiving them, or are not dwelling in a fool’s paradise.
— Winston Churchill

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Immunity conferred by influenza virus vaccine is short-lived. After immunization with inactivated influenza virus vaccine, serum antibody levels peak within a few months and then decline rapidly. This decline was recently shown to be caused by loss of bone marrow plasma cells, a major source of serum antibodies. Results of a recent study partially address the relevance of this observation to infection with SARS-CoV-2.

After immunization, antigen-specific B cells produced in the periphery give rise to antibody-producing plasma cells. Some of these B cells migrate to the bone marrow where they remain for many years and serve as a source of anti-viral antibodies to protect against infection or disease. Such bone marrow plasma cells are produced after immunization with inactivated influenza virus vaccine, but they are lost within a year.

An important question raised by these findings is whether immunization with SARS-CoV-2 vaccines will produce short or long-lived bone marrow plasma cells. It is too soon to know the answer but clues are provided by a study of patients previously infected with SARS-CoV-2. Examination of serum antibodies to the virus in symptomatic and recovered patients revealed a rapid rise in levels of anti-spike protein antibodies shortly after onset of symptoms. However within months the antibody levels declined to baseline levels observed in control patients.

To determine if antibody-secreting cells persist longer, virus-specific memory B cells and plasmablasts (the precursors of antibody secreting plasma cells) were isolated from patient blood. In contrast to the observed decay of serological antibody memory, the B cells and plasmablasts were stable for up to 6 months following recovery from COVID-19.

These observations suggest that virus-specific B cells should be available to provide anti-viral antibodies in the event of reinfection. Whether these B cells persist for longer than 6 months needs to be determined by additional studies. More importantly, this study did not address whether bone marrow plasma cells persist long after infection, a question that could be answered once SARS-CoV-2 vaccines are licensed and used.

By David Tuller, DrPH

It is clear that there will be much grappling going forward over the similarities and differences between long-Covid and ME (or CFS, or ME/CFS, or whatever this illness or cluster of illnesses is being called). The two entities overlap in some ways, but no one should conflate them.

We are past the pandemic’s half-year mark. Since most (but not all) case definitions in the ME and CFS category require symptoms to be present for six months, some long-Covid patients, called long-haulers, might already meet diagnostic criteria for the disease. But many clearly suffer from symptoms and organ damage not associated with ME and its variants.

[continue reading…]

Ralph Baric returns to TWiV to provide an update on the COVID-19 resurgence in the US, monoclonal antibodies, antiviral drugs, vaccines, immunity and reinfection, reopening schools, and what will happen this fall.

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Daniel Griffin provides a clinical report on COVID-19, then we discuss decline of virus-specific bone marrow B cells within a year after influenza vaccination, the push to release SARS-CoV-2 vaccines before completion of phase 3 trials, and absence of evidence for infectious virus in aerosols.

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Download TWiV 660 (95 MB .mp3, 159 min)
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Show notes at microbe.tv/twiv