virology blog – Page 4

Trial By Error: Journal of Health Psychology Publishes Hughes-Tuller Critique of Wessely-Chalder CBT Claims

10 April 2021 by David Tuller

By David Tuller, DrPH

What kind of researchers would publish obviously misleading figures about their favorite intervention in a study abstract? And who would make causal claims in a paper while simultaneously pointing out that the study design does not allow for causal claims? Well, it seems Professor Sir Wessely and Professor Trudie Chalder, along with three of their colleagues from King’s College London, would do both of those things.

Another question is why would the purportedly rigorous Journal of the Royal Society of Medicine publish a paper that included misleading figures in a study abstract and made unwarranted causal claims? What happened with the peer review process that such obvious failings were not noticed, or not revised if they were? Did the journal recognize that it would need to be especially rigorous when reviewing a paper co-authored by the sponsoring society’s immediate past president, and that any weaknesses exposed later on would reflect especially badly on all involved?

A tapeworm drug to treat COVID-19?

8 April 2021 by Vincent Racaniello

Niclosamide (pictured) is a drug that has been approved in humans to treat infections with a variety of tapeworms. It might be useful for preventing SARS-CoV-2 replication and COVID-19 pathogenesis by inhibiting virus-catalyzed membrane fusion.

Examination of the lungs of 41 patients who died of COVID-19 revealed, in addition to expected lung injury, the presence of syncytia. Such giant cells contain many nuclei and are produced when SARS-CoV-2 infected cells fuse with neighboring, uninfected cells. The fusion occurs when the spike protein of SARS-CoV-2, present on the plasma membrane of infected cells, attaches to the receptor ACE2 on a neighboring cell. This interaction would normally allow virus particles to fuse on entry into cells. In this case, the interaction leads to fusion of neighboring cells. Production of only the spike protein in cells in culture also leads to formation of syncytia.

These observations suggested that a drug that inhibits syncytium formation might help alleviate the severe lung injury observed in some COVID-19 patients. Screening of over 3000 small molecules for their ability to inhibit cell fusion identified a variety of candidates which had in common the ability to regulate intercellular calcium levels. Some of these compounds, such as Niclosamide, inhibited both membrane fusion and virus reproduction.

Niclosamide is an inhibitor of the calcium-activated TMEM16 family of chloride channels. Production of spike in SARS-CoV-2 infected cells leads to activation of TMEM16, which is required for syncytium formation. These observations explain why inhibition of TMEM16 by niclosamide impairs formation of syncytia.

Based on its known activities, activation of TMEM16 by SARS-CoV-2 infection might not only stimulate formation of syncytia, but could also promote inflammation, thrombosis, and diarrhea, the latter through promotion of chloride secretion from cells. Hence the drug might be useful for treating COVID-19 disease and might have efficacy later in infection when antivirals are not effective.

Trial By Error: Prof Sharpe Fact-Checks Comment on Blog About How George Monbiot Is Causing Long COVID

7 April 2021 by David Tuller

By David Tuller, DrPH

*April is crowdfunding month at Berkeley. I conduct this project as a senior fellow in public health and journalism at the university’s Center for Global Public Health. If you would like to support the project with a donation to Berkeley (tax-deductible for US taxpayers), here’s the place: https://crowdfund.berkeley.edu/project/25504

In a surprising development, Professor Michael Sharpe has left a comment on a blog I posted yesterday. The blog was about Professor Sharpe’s apparent belief that Guardian columnist George Monbiot and Long COVID support groups, among others, are causing the wave of prolonged symptoms being reported by many thousands of people after confirmed or presumed cases of COVID-19.

Trial By Error: Guardian Columnist George Monbiot Is Causing Long COVID, Says Professor Michael Sharpe

6 April 2021 by David Tuller

By David Tuller, DrPH

*April is crowdfunding month at Berkeley. I conduct this project as a senior fellow in public health and journalism and the university’s Center for Global Public Health. If you would like to support the project, here’s the place: https://crowdfund.berkeley.edu/project/25504

In a remarkable display of—well, I’m not even sure what to call it–Professor Michael Sharpe has blamed Guardian columnist George Monbiot and Long COVID support groups, among others, for the wave of people reporting prolonged symptoms after acute bouts of COVID-19. And during the same February presentation in which he made those observations, Professor Sharpe warned viewers of “poor quality research” while still citing his beloved but discredited PACE trial as if it offered meaningful evidence. The event was an “Expert Forum on secondary COVID-19 impacts” organized by Swiss Re, a major reinsurance company.

Trial By Error: Northwestern Law Professor Steve Lubet’s View of that Wall Street Journal Editorial

6 April 2021 by David Tuller

By David Tuller, DrPH

I’ve already posted my thoughts about the ill-informed opinion piece by a psychiatrist-in-training that The Wall Street Journal published two weeks ago. The author’s dismissal of the Long COVID phenomenon as a result of delusions and mental illness elicited a lot of sharp responses online. The Wall Street Journal itself published a strong rebuttal from one of the author’s peers–a psychiatric resident in New York. He answered a few of my questions here.

My friend and colleague Steve Lubet, a law professor at Northwestern University in Chicago, wrote his own response, which was posted today on a site called Social Science Space. Here’s a description of the site itself: “Social Science Space brings social scientists together to explore, share and shape the big issues in social science, from funding to impact. This online social network features blogs with the most current thinking from key players in social science, a forum for discussions, a resource center with free videos, reports and slides that support these discussions, as well as funding and job opportunity notices.“

You can read Professor Lubet’s article at Social Science Space here. I have also re-posted it in full below, with his permission.

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Trial By Error: GETSET Study Reports Null Results for Self-Help Graded Exercise–but Declares Success Anyway

6 April 2021 by David Tuller

By David Tuller, DrPH

The Journal of Psychosomatic Research (JSR), an influential publication. recently published an article that made a crucial point—in clinical trials, subjective outcomes are at “a greater risk of bias due to any unblinding.” The article, which I wrote about here, was authored by the journal’s current editor and two previous editors, both of whom are still on the journal’s advisory board.

The article involved whether or not a well-blinded clinical trial of homeopathy, which the journal had published years earlier, should be retracted. The details were complex and of little consequence here, beyond this: The journal’s decision not to retract the study rested on the assessment that the blinding remained robust despite one investigator’s efforts to undermine it. Given the article’s editorial provenance, it would likely be fair to assume the following passage represents the journal’s position:

Trial By Error: Long COVID, the Long COVID Alliance, and ME International

4 April 2021 by David Tuller

By David Tuller, DrPH

The advent of Long COVID has brought an enormous amount of attention to the illness or cluster of illnesses collectively known these days as ME/CFS. That attention is not always positive, as we saw recently with a Wall Street Journal opinion piece that dismissed both ME/CFS and Long COVID as forms of mental illness. The trainee-psychiatrist who penned that piece of crap even referred to PACE as representing the “prevailing view” of the medical profession.

Many other articles have explored the overlaps between Long COVID and ME/CFS in more thoughtful ways. A major problem, of course, is that both categories grapple with definitional issues. What has been dubbed Long COVID has been officially named “post-acute sequelae of COVID-19” (PASC), which at least recognizes that the term covers a diversity of symptoms and conditions. With ME and ME/CFS, various currently used definitions—the 2003 Canadian Consensus Criteria for ME/CFS, the 2011 International Consensus Criteria for ME, and the US Centers for Disease Control and Prevention’s 2015 definition for what it called “systemic exertion intolerance disease”–identify different albeit overlapping populations. That can create difficulties in implementing studies and interpreting the findings.

Trial By Error: More on that WSJ Opinion Piece; and Q-and-A with Author of this Week’s WSJ Rebuttal

2 April 2021 by David Tuller

By David Tuller, DrPH

Last week, The Wall Street Journal published a passionate but clueless opinion piece from a psychiatric resident at McMaster University in Ontario, Canada. The author, Jeremy Devine, portrayed the entire category now being referred to as Long COVID as a fiction foisted on the world by a committed commando of deluded and illness-obsessed queer feminists (or maybe queers and feminists–I’m not sure). And patients, no less! The column’s mean-spirited tone made it difficult to read. Repellent, actually. I wrote about it here.

Are the SARS-CoV-2 Vaccines Safe for Pregnant and Lactating People?

1 April 2021 by Gertrud U. Rey

by Gertrud U. Rey

Vaccination is the gold standard for preventing infectious diseases and reducing the impact of emerging pathogens. As more and more people are becoming immunized against SARS-CoV-2, a prominent question continues to arise: are the vaccines safe for pregnant and breast-feeding people?

(Image credit: Shutterstock)

None of the clinical trials for SARS-CoV-2 vaccines included pregnant or lactating subjects. Pregnant people in particular are a historically difficult group to study in the context of drug safety because of concerns of liability over potential adverse effects of a new product on a fetus. This lack of safety data further complicates treatment of SARS-CoV-2 infection in pregnant people, who already have an increased risk for premature birth and miscarriage if they become infected. Based on these risk factors, the currently available data, and interim recommendations by the Advisory Committee on Immunization Practices for people over the age of 16, the American College of Obstetricians and Gynecologists recommends that pregnant and lactating people should have access to SARS-CoV-2 vaccines. Fortunately, many pregnant and lactating people have opted to be vaccinated, and the data on the safety and efficacy of vaccination in these two cohorts are beginning to emerge.

A recent publication in the American Journal of Obstetrics and Gynecology describes the safety and immunogenicity of SARS-CoV-2 vaccines in pregnant and lactating women compared to non-pregnant controls and women who had been naturally infected with SARS-CoV-2 during pregnancy. The researchers collected blood and breast milk from 131 women of reproductive age, including 84 pregnant, 31 lactating, and 16 non-pregnant participants who had received two doses of either the Pfizer/BioNTech or Moderna mRNA COVID-19 vaccine; and analyzed the samples for the presence of IgG and IgA antibodies. IgG antibodies are mostly present in the blood and provide the majority of antibody-based immunity against invading pathogens. IgA antibodies are predominantly found in mucus membranes and the fluids secreted by these membranes, including saliva, tears, and breast milk. IgA antibodies are particularly suitable for protecting against pathogens like SARS-CoV-2, which invade the body through these membranes.

Samples were collected at the time of the first and second vaccination, 2 to 6 weeks after the second dose, and at delivery. The researchers also collected umbilical cord blood from 10 infants born during the study period.

The main findings were as follows. Side effects resulting from vaccination were rare and occurred with similar frequency in all participants. These findings are consistent with post-vaccination data tracked by the CDC via the V-safe application, suggesting that post-vaccination reactions in pregnant people are not significantly different from those in non-pregnant people.

Pregnant, lactating, and non-pregnant vaccine recipients produced significantly higher levels of SARS-CoV-2-specific IgG than pregnant women who had been naturally infected. Interestingly, the second vaccine dose led to increased concentrations of coronavirus-specific IgG but not IgA, in both maternal blood and breast milk. The authors speculate that this lack of IgA boosting may have to do with the intramuscular route of immunization, which usually does not induce very high levels of serum IgA. The role of IgA in the serum is mostly secondary to IgG, in that IgA mediates elimination of pathogens that have breached the mucosal surface. In contrast, natural infection induces higher levels of mucosal (IgA) antibodies because SARS-CoV-2 enters the body through the mucosal surfaces. Nevertheless, studies have shown that IgG in breast milk is critical for protecting newborns from other pathogens like HIV, RSV, and influenza. It is possible that this type of antibody is equally important for protecting infants from SARS-CoV-2.

It was previously unclear whether vaccine-induced SARS-CoV-2 antibodies are transferred across the placenta to the fetus. However, the authors also found vaccine-induced IgG in cord blood, suggesting that these antibodies do cross the placenta, as has been previously observed after vaccination of pregnant people against influenza virus, Bordetella pertussis, and other pathogens. Whether these antibodies protect the baby from SARS-CoV-2 infection after birth, remains to be determined.

This study provides the first set of clinical data suggesting that vaccination of pregnant and lactating people against SARS-CoV-2 is both safe and beneficial. Some people have expressed concern over the possible incidence of fever following the second vaccine dose in pregnant people; however, the potential risk to the fetus from a 24-hour fever must be weighed against the possibility of chronic, severe COVID-19 in the mother. Accumulating data suggest that the benefits of vaccination during pregnancy and lactation outweigh the risks of adverse effects to the fetus or infant and align with the abundance of clinical data showing the beneficial effects of vaccinating these groups of people against influenza virus. Analyses of cord blood from infants whose mothers were naturally infected with SARS-CoV-2 during pregnancy indicate that the potential for transfer of antibodies is greater early during gestation, suggesting that immunization during the earlier stages of pregnancy might be preferable. However, more studies are needed to assess the optimal timing of maternal vaccination to achieve enhanced neonatal immunity. In the meantime, these preliminary data allow pregnant and lactating people to make more informed decisions, and also aid physicians in providing evidence-based recommendations.

T cells will save us from COVID-19

25 March 2021 by Vincent Racaniello

In our quest to stop the COVID-19 pandemic by vaccination, we have been myopically focussed on inducing antibodies against the spike protein. As variants of SARS-CoV-2 have emerged that reduce the ability of such antibodies to block infection, concern has arisen that we will not be able to halt the disease. Such concerns appear to ignore the other important arm of the adaptive immune response: T cells.

Anti-viral antibodies can prevent infection of cells, but when antibody titers are low – years after infection or vaccination – some cells will inevitably be infected. In this case, T cells come to the rescue. Cytotoxic T cells can sense that a cell is infected and kill it (illustrated). T cells sense infected cells by virtue of viral peptides that are presented by major histocompatibility molecules on the plasma membrane. Such T cell peptides may be produced from nearly any viral protein. In contrast, only certain viral proteins, like the spike of SARS-CoV-2, can give rise to antibodies that block infection.

The T cell response to SARS-CoV-2 infection has been largely ignored for the past year. Certainly, some laboratories have studied T cell responses in patients, and the vaccine makers have dutifully included them along with assays for neutralizing antibodies. But the dialogue has never included T cells as important for resolving disease – but they are for most viral infections. Because T cells can kill virus infected cells, they can help prevent disease and end the infection.

The recent finding that amino acid changes in the spike protein of SARS-CoV-2 variants of concern do not impact T cell reactivity is very good news. In this study, the authors synthesized short peptides covering the entire proteome of multiple SARS-CoV-2 isolates, including the original Wuhan strain, and variants B.1.1.7, B.1.351, P.1, and CAL.20C. They found little difference in the ability of T cells from either convalescent or vaccinated patients to recognize peptides from these viruses. This result means that the amino acid changes in the variants are not likely to impact the ability of T cells to clear infection.

This observation explains why some COVID-19 vaccines have effectively prevented hospitalization and death even in regions where variants circulate widely. In some cases the ability of sera from vaccinated individuals have reduced ability to neutralize infection with some variants. Nevertheless, the vaccines prevent severe COVID-19 and death because T cells can still recognize variant virus-infected cells and clear them.

It’s highly unlikely that vaccination will prevent infection with SARS-CoV-2. Antibody levels rapidly decline after infection or vaccination, especially in the respiratory mucosa. When a virus enters the nasopharynx of an immune individual, it will encounter little antibody opposition and will initiate an infection. However memory B and T cells will spring into action and within a few days produce virus-specific antibodies and T cells. The antibodies will limit infection while the T cells will clear the virus-infected cells. The result is a mild or asymptomatic infection that likely is not transmitted to others.

The recent observations that vaccination appears to prevent asymptomatic infections is a red herring. These studies are being done soon after vaccination when antibody levels in serum and mucosa are high. If these studies were done a year after immunization, the results would be quite different.

Now imagine that you are fully vaccinated and become infected with a SARS-CoV-2 variant. The virus may begin to reproduce rather well in the nasopharynx even in the face of a memory response, because the antibodies are just not good enough to block infection. T cells to the rescue: the T cell epitopes on the surface of the infected cells are readily recognized because they are mainly the same in the variants as in the ancestral strain of SARS-CoV-2. You may have a mild infection but you will not be hospitalized or die. Isn’t that the goal of vaccination?

Why don’t T cell epitopes change as do B cell (antibody) epitopes? A B cell epitope is the same in everyone and so if a virus emerges with a slightly different epitope, it will evade antibody in anyone infected with that virus. T cell epitopes are different. T cell epitopes are presented to T cells on the infected cell surface by MHC molecules, which are encoded by highly polymorphic genes. That means that your MHC is likely different from mine, and so will be the viral peptides displayed in them. So if a T cell epitope varies during your infection, it won’t matter to other people – their infected cells will be displaying different T cell peptides.

It is possible that SARS-CoV-2 will continue to produce altered spike proteins that will completely evade antibody neutralization. In this case T cells might not be enough to prevent severe disease – they could be overwhelmed by so many infected cells. Our rush to make vaccines – understandable given the urgency – have led us to such a situation. Most of the vaccines were based only on the spike protein. If we change the spike protein to accommodate variants, we might get in a never-ending cycle of changing COVID-19 vaccines on a regular basis. A better approach would be to produce second-generation COVID vaccines that include other viral proteins besides spike protein. Inactivated and attenuated vaccines fall into this category; another solution would be to modify authorized mRNA vaccines to encode additional viral proteins.

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